[go: up one dir, main page]

WO2025068896A1 - Composés et méthodes pour réduire l'expression de psd3 - Google Patents

Composés et méthodes pour réduire l'expression de psd3 Download PDF

Info

Publication number
WO2025068896A1
WO2025068896A1 PCT/IB2024/059334 IB2024059334W WO2025068896A1 WO 2025068896 A1 WO2025068896 A1 WO 2025068896A1 IB 2024059334 W IB2024059334 W IB 2024059334W WO 2025068896 A1 WO2025068896 A1 WO 2025068896A1
Authority
WO
WIPO (PCT)
Prior art keywords
mrn
frn
double
nucleobase
seq
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/059334
Other languages
English (en)
Inventor
Anders DAHLÈN
Maxim Ivanov
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
AstraZeneca AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2025068896A1 publication Critical patent/WO2025068896A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering nucleic acids [NA]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/317—Chemical structure of the backbone with an inverted bond, e.g. a cap structure
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/322—2'-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/344—Position-specific modifications, e.g. on every purine, at the 3'-end
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/351—Conjugate

Definitions

  • an oligonucleotide comprising a nucleoside comprising a 2’-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2’- OH in place of one 2’-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA).
  • nucleic acid sequences provided herein, including, but not limited to those in the sequence listing are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, unless otherwise stated, including, but not limited to such nucleic acids having modified nucleobases.
  • FIELD Provided are double-stranded oligonucleotides, polynucleotide conjugates, and compositions and populations comprising the same, as well as methods and uses thereof for reducing the amount or activity of Pleckstrin and Sec7 Domain Containing 3 (PSD3) RNA in a cell or animal, and in certain instances reducing the amount of PSD3 protein in a cell or animal.
  • PSD3 Pleckstrin and Sec7 Domain Containing 3
  • Such double-stranded oligonucleotides, polynucleotide conjugates, and compositions and populations, methods and uses are useful to treat liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis hereditary hemochromatosis
  • hereditary hemochromatosis hereditary hemochromatosis
  • Non-alcoholic fatty liver disease covers a spectrum of liver disease from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis.
  • NAFLD nonalcoholic steatohepatitis
  • NAFLD is defined as fat accumulation in the liver exceeding 5% by weight, in the absence of significant alcohol consumption, steatogenic medication, or hereditary disorders (Kotronen et al, Arterioscler Thromb. Vasc. Biol.2008, 28: 27-38).
  • NAFLD nonalcoholic steatohepatitis
  • NAFLD Non-alcoholic steatohepatitis
  • NASH is defined histologically by macrovesicular steatosis, hepatocellular ballooning, and lobular inflammatory infiltrates (Sanyal, Hepatol. Res.2011.41: 670-4). NASH is estimated to affect 2-3% of the general population. In the presence of other pathologies, such as obesity or diabetes, the estimated prevalence increases to 7% and 62% respectively (Hashimoto et al, J. Gastroenterol.2011.46(1): 63-69). PSD3 downregulation by antisense oligonucleotides in vivo protects against fatty liver disease in mice fed on a non-alcoholic steatohepatitis-inducing diet (Nature Metabolism 2022, 4: 60-75).
  • the present invention provides a double-stranded oligonucleotide comprising an antisense strand comprising a nucleobase sequence that is at least 80% complementary to an equal length portion of a PSD3 nucleic acid having the nucleobase sequence of SEQ ID NO: 1, and a sense strand.
  • the antisense strand may comprise a nucleobase sequence that is at least 80% complementary to an equal length portion within a nucleobase sequence corresponding to nucleobases 1 to 8100, particularly 1 to 600, 1400 to 3500 or 7500 to 8100 of SEQ ID NO: 1.
  • the antisense strand may comprise a nucleobase sequence that is at least 85%, at least 90%, at least 95%, or 100% complementary to said equal length portion within a nucleobase sequence corresponding to nucleobases 1 to 8100, particularly 1 to 600, 1400 to 3500 or 7500 to 8100 of SEQ ID NO: 1.
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 85%, at least 90%, at least 95%, or 100% identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 17
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21,at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146
  • the nucleobase sequence of the antisense strand may comprise the nucleobase sequence of any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 182, 183, 186, 187,
  • the nucleobase sequence of the antisense strand may consist of the nucleobase sequence of any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 182, 183, 186, 187
  • the sense strand may comprise a nucleobase sequence that is at least 80% identical to said equal length portion within a nucleobase sequence corresponding to nucleobases 1 to 8100, particularly 1 to 600, 1400 to 3500 or 7500 to 8100 of SEQ ID NO: 1.
  • the sense strand may comprise a nucleobase sequence that is at least 85%, at least 90%, at least 95%, or 100% identical to said equal length portion within a nucleobase sequence corresponding to nucleobases 1 to 8100, particularly 1 to 600, 1400 to 3500 or 7500 to 8100 of SEQ ID NO: 1.
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 85%, at least 90%, at least 95%, or 100% identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of the nucleobase sequences of any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153,
  • the nucleobase sequence of the sense strand may comprise the nucleobase sequence of any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184, 185, 188, 189, 192
  • the nucleobase sequence of the sense strand may consist of the nucleobase sequence of any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184, 185, 188, 189,
  • the nucleobase sequence of the antisense strand may consist of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides; and/or (b) the nucleobase sequence of the sense strand may consist of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides.
  • the nucleobase sequence of the antisense strand may consist of between 19 to 23 linked nucleosides and the nucleobase sequence of the sense strand may consist of between 19 to 23 linked nucleosides.
  • the nucleobase sequence of the antisense strand may consist of between 19 to 23 linked nucleosides and the nucleobase sequence of the sense strand may consist of between 19 to 21 linked nucleosides.
  • the 3’ end of the antisense strand may overhang the sense strand by between about 0 to about 6 nucleosides, preferably by about 2 nucleosides.
  • the antisense strand and/or the sense strand may comprise at least one modification optionally selected from a modified sugar moiety and/or a modified internucleoside linkage.
  • the antisense strand and/or the sense may comprise at least one modified sugar moiety.
  • Said modified sugar moiety may comprise a non-bicyclic sugar moiety.
  • the non-bicyclic modified sugar moiety may be a 2’-OMe modified sugar moiety and/or a 2’-fluoro modified sugar moiety.
  • the antisense strand and/or the sense strand may comprise at least one modified internucleoside linkage.
  • Said at least one modified internucleoside linkage may be a phosphorothioate internucleoside linkage.
  • the antisense strand and/or the sense strand preferably both the antisense strand and the sense strand, may comprises at least one phosphodiester internucleoside linkage.
  • Each internucleoside linkage of the antisense strand and/or the sense strand may be independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.
  • oligonucleotide of the invention (a) at least 1, at least 2, at least 3, at least 4, at least 5 or more of the internucleoside linkages of the antisense strand may be phosphorothioate internucleoside linkages, preferably wherein 4 of the internucleoside linkages of the antisense are phosphorothioate internucleoside linkages; and/or (b) at least 1, at least 2, at least 3, at least 4, at least 5 or more of the internucleoside linkages of the sense strand may be phosphorothioate internucleoside linkages, preferably wherein 4 of the internucleoside linkages of the sense strand are phosphorothioate internucleoside linkages; wherein preferably 4 of the internucleoside linkages of the sense strand and 4 of the internucleoside linkages of the antisense strand are phosphorothioate internucleoside linkages.
  • the antisense strand may comprise at least two consecutive modified internucleoside linkages at the 5’ end; and/or the antisense strand may comprise at least two consecutive modified internucleoside linkages at the 3’ end.
  • the sense strand may comprise at least two consecutive modified internucleoside linkages at the 5’ end; and/or the sense strand may comprise at least two consecutive modified internucleoside linkages at the 3’ end.
  • the antisense strand may comprise: (a) 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN ][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][mRN][mRN][fRN][mRN][mRN][mRN][mRN][fRN][mR N][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mR N][fRN][mRN][
  • the two 5’ most internucleoside linkages of the antisense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of the antisense strand may be phosphorothioate internucleoside linkages.
  • the sense strand may comprise: (a) 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][m
  • the two 5’ most internucleoside linkages of the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleotide and [fRN] stands for a 2’-fluoro modified nucleotide.
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][fRN][mRN][mRN][fRN][mR N][fRN][mRN][fRN][mRN][fRN][mRN]3’; and the sense strand may comprise 5’[fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN] [fRN][mRN] [fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleotide and [fRN] stands for a 2’- fluoro modified nucleotide.
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][mRN][fRN][mR N][fRN][mRN][fRN][mRN][mRN][mRN]3’; and the sense strand may comprise 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’[mRN][fRN][mRN][mRN][mRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; and the sense strand may comprise 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; wherein [mRN] stands for a 2’-
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise 5’[mRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; and the sense strand may comprise 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleot
  • the two 5’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of both the antisense strand and the sense strand may be phosphorothioate internucleoside linkages.
  • the antisense strand may comprise a 5’ 5- vinylphosphonate (5VP) modification.
  • the antisense strand and/or the sense strand may comprise at least one modified nucleobase, optionally selected from 5-methylcytosine or methyl-uracil.
  • the invention also provides a polynucleotide conjugate comprising a double-stranded oligonucleotide of the invention and a conjugate group.
  • the conjugate group may comprise a conjugate linker and a conjugate moiety.
  • the conjugate linker may consist of a single bond.
  • the conjugate linker may be cleavable.
  • the conjugate linker may comprise 1-3 linker- nucleosides.
  • the conjugate linker may be a phosphate.
  • the conjugate group may be attached to the modified oligonucleotide at the 5’-end of the modified oligonucleotide.
  • the conjugate group may be attached to the modified oligonucleotide at the 3’-end of the modified oligonucleotide.
  • the conjugate group may comprise N- acetyl galactosamine (GalNAc).
  • the GalNAc may be present at the 5’ and/or the 3’ of (i) the antisense strand and/or (ii) the sense strand.
  • the GalNAc is present at the 5’ and/or 3’ end of the sense strand, more preferably at the 3’ end of the sense strand.
  • the conjugate group may have the following structure: .
  • the conjugate group may comprise a cell-targeting moiety.
  • the polynucleotide conjugate may comprise a terminal group.
  • the terminal group may be an abasic sugar moiety.
  • the invention also provides a chirally enriched population of double-stranded oligonucleotide or polynucleotide conjugate of the invention, wherein the population is enriched for double-stranded oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • the chirally enriched population may be enriched for double-stranded oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) or (Rp) configuration, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • the chirally enriched population may be enriched for double-stranded oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • the chirally enriched population may be enriched for double-stranded oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • the chirally enriched population may be enriched for double-stranded oligonucleotides having at least 2 or at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5’ to 3’ direction, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • all of the phosphorothioate internucleoside linkages of the double-stranded oligonucleotides may be stereorandom.
  • the invention further provides a pharmaceutical composition comprising a double-stranded oligonucleotide, polynucleotide conjugate, or population of the invention, and a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutically acceptable diluent may be water or phosphate-buffered saline.
  • the pharmaceutical composition may consist essentially of a double-stranded oligonucleotide, polynucleotide conjugate, or population of the invention, and water or phosphate-buffered saline.
  • the invention also provides a method comprising administering to a subject a double-stranded oligonucleotide, a polynucleotide conjugate, a population, or a pharmaceutical composition of the invention.
  • the invention further provides a method of treating a disease associated with PSD3 comprising administering to a subject having a disease associated with PSD3 a therapeutically effective amount of a double- stranded oligonucleotide, a polynucleotide conjugate, a population, or a pharmaceutical composition of the invention; thereby treating the disease associated with PSD3.
  • the disease associated with PSD3 may be liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis hereditary hemochromatosis
  • primary sclerosing cholangitis may be primary sclerosing cholangitis.
  • Administering a double-stranded oligonucleotide, a polynucleotide conjugate, a population, or a pharmaceutical composition of the invention may reduce liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation in the subject.
  • the invention also provides a method of reducing expression of PSD3 in a cell comprising contacting the cell with a double-stranded oligonucleotide, a polynucleotide conjugate, a population, or a pharmaceutical composition of the invention.
  • the cell may be a liver cell.
  • the invention further provides the use of a double-stranded oligonucleotide, a polynucleotide conjugate, a population, or a pharmaceutical composition of the invention for treating a disease associated with PSD3.
  • the invention also provides the use of a double-stranded oligonucleotide, a polynucleotide, a population, or a pharmaceutical composition of the invention in the manufacture of a medicament for treating a disease associated with PSD3.
  • the disease associated with PSD3 may be liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis hereditary hemochromatosis
  • primary sclerosing cholangitis may be primary sclerosing cholangitis.
  • the invention further provides a double-stranded oligonucleotide, a polynucleo
  • the disease associated with PSD3 may be liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis chronic hepatitis
  • hereditary hemochromatosis hereditary hemochromatosis
  • primary sclerosing cholangitis may be primary sclerosing cholangitis.
  • Figure 1 Schematic of preferred modification patterns for antisense strands of the invention.
  • Figure 2 Schematic of preferred modification patterns for sense strands of the invention.
  • the term “capable of” when used with a verb encompasses or means the action of the corresponding verb.
  • “capable of interacting” also means interacting
  • “capable of cleaving” also means cleaves
  • “capable of binding” also means binds and "capable of specifically targeting" also means specifically targets.
  • Numeric ranges are inclusive of the numbers defining the range. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed.
  • the term “about” shall be understood herein as plus or minus ( ⁇ ) 5%, preferably ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, ⁇ 0.1%, of the numerical value of the number with which it is being used.
  • the term “consisting of''” refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the invention.
  • the term “consisting essentially of'' refers to those elements required for a given invention. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that invention (i.e., inactive or non-immunogenic ingredients).
  • Embodiments described herein as “comprising” one or more features may also be considered as disclosure of the corresponding embodiments “consisting of” and/or “consisting essentially of” such features.
  • Concentrations, amounts, volumes, percentages and other numerical values may be presented herein in a range format. It is also to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited.
  • the polynucleotides of the present invention may be prepared by any means known in the art.
  • polynucleotides of the present invention may preferably be produced by chemical synthesis, e.g., by the phosphoramidite method or the tri-ester method and may be performed on commercial automated oligonucleotide synthesizers.
  • a double-stranded oligonucleotide may be obtained from the single stranded product of chemical synthesis either by synthesizing the complementary strand and annealing the strand together under appropriate conditions or by adding the complementary strand using DNA polymerase with an appropriate primer sequence.
  • a “variant” nucleic acid sequence has substantial homology or substantial similarity to a reference nucleic acid sequence (or a fragment thereof).
  • a nucleic acid sequence or fragment thereof is “substantially homologous” (or “substantially identical”) to a reference sequence if, when optimally aligned (with appropriate nucleotide insertions or deletions) with the other nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 70%, 75%, 80%, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 99/5, 99.9 or more% of the nucleotide bases. Methods for homology determination of nucleic acid sequences are known in the art.
  • a “variant” nucleic acid sequence is substantially homologous with (or substantially identical to) a reference sequence (or a fragment thereof) if the “variant” and the reference sequence they are capable of hybridizing under stringent (e.g., highly stringent) hybridization conditions.
  • Nucleic acid sequence hybridization will be affected by such conditions as salt concentration (e.g. NaCl), temperature, or organic solvents, in addition to the base composition, length of the complementary strands, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art.
  • Stringent temperature conditions are preferably employed, and generally include temperatures in excess of 30°C, typically in excess of 37°C and preferably in excess of 45°C.
  • Stringent salt conditions will ordinarily be less than 1000 mM, typically less than 500 mM, and preferably less than 200 mM.
  • the pH is typically between 7.0 and 8.3.
  • Methods of determining nucleic acid percentage sequence identity are known in the art. By way of example, when assessing nucleic acid sequence identity, a sequence having a defined number of contiguous nucleotides may be aligned with a nucleic acid sequence (having the same number of contiguous nucleotides) from the corresponding portion of a nucleic acid sequence of the present invention.
  • Tools known in the art for determining nucleic acid percentage sequence identity include Nucleotide BLAST (as described below).
  • the terms “decrease” “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount.
  • the terms “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g.
  • “reduction” or “inhibition” encompasses a complete inhibition or reduction as compared to a reference level.
  • “Complete inhibition” is a 100% inhibition (i.e., abrogation) as compared to a reference level.
  • the terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 25%, at least 50% as compared to a reference level, for example an increase of at least about 50%, or at least about 75%, or at least about 80%, or at least about 90%, at least about 95%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 250% or more compared with a reference level, or at least about a 1.5-fold, or at least about a 2-fold, or at least about a 2.5-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 1.5-fold and 10- fold or greater as compared to a reference level.
  • 2’-deoxynucleoside means a nucleoside comprising a 2’-H(H) deoxyfuranosyl sugar moiety.
  • a 2’-deoxynucleoside is a 2’- ⁇ -D-deoxynucleoside and comprises a 2’- ⁇ -D- deoxyribosyl sugar moiety, which has the ⁇ -D ribosyl configuration as found in naturally occurring deoxyribonucleic acids (DNA).
  • a 2’-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).
  • xeno nucleic acid and “XNA” means a nucleic acid with a backbone constructed from sugars that are distinct from the natural ribose sugars found in RNA.
  • the term XNA includes, but is not limited to unlocked nucleic acids (UNA), glycol nucleic acids (GNA), DNA, 2'-deoxy-2'-fluoro-arabinonucleic acids (2’F-ANA), threose nucleic acids (TNA), serinol nucleic acids (SNA), flexible nucleic acids (FNA), 2’NH 2 -RNA, 1’,2’-seco-DNA, 3(S),5-dihydroxypentyl nucleic acids, and nucleoside analogues comprising a six-membered tetrahydropyran (THP, e.g.
  • THP six-membered tetrahydropyran
  • XNA a hexitol nucleic acid
  • ANA arabinonucleic acid
  • MNA mannitol nucleic acid
  • Preferred XNAs include GNA, UNA and DNA.
  • unlocked nucleic acid and UNA mean an acyclic derivative of RNA lacking the C2'- C3'-bond of the ribose ring of RNA.
  • Glycol nucleic acid and “GNA” mean a nucleic acid in which a propylene glycol group is in place of the ribose or deoxyribose sugar moiety.
  • 2'-deoxy-2'-fluoro-arabinonucleic acid and “2’F-ANA” refers to a nucleic acid in which the 2’-OH has been inverted and fluorinated.
  • threose nucleic acid and “TNA” mean (3’ ⁇ 2’)- ⁇ -L-threose nucleic acid, in which the backbone repeat unit is one atom shorter than in RNA or DNA.
  • serinol nucleic acid and “SNA” mean a nucleic acid in which a serinol (2-amino-1,3- propanediol) group is in place of the ribose or deoxyribose sugar moiety.
  • flexible nucleic acid and “FNA” mean a nucleic acid in which a glycerol group is in place of the ribose or deoxyribose sugar moiety.
  • 2’NH2-RNA means a nucleic acid in which the 2'-OH group of the ribose moiety is replaced by a 2'-amino (2'-NH2) group.
  • 2’-MOE means a 2’-OCH2CH2OCH3 group in place of the 2’-OH group of a furanosyl sugar moiety.
  • a “2’-MOE sugar moiety” means a sugar moiety with a 2’-OCH 2 CH 2 OCH 3 group in place of the 2’-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2’-MOE sugar moiety is in the ⁇ -D- ribosyl configuration.
  • MOE means O-methoxyethyl.
  • 2’-MOE nucleoside means a nucleoside comprising a 2’-MOE sugar moiety.
  • 2’-OMe means a 2’-OCH3 group in place of the 2’-OH group of a furanosyl sugar moiety.
  • a “2’-O-methyl sugar moiety” or “2’-OMe sugar moiety” means a sugar moiety with a 2’-OCH 3 group in place of the 2’-OH group of a furanosyl sugar moiety.
  • a 2’-MOE sugar moiety is in the ⁇ -D-ribosyl configuration.
  • 2’-OMe nucleoside means a nucleoside comprising a 2’-OMe sugar moiety.
  • 2’-substituted nucleoside means a nucleoside comprising a 2’-substituted sugar moiety.
  • 2’-substituted in reference to a sugar moiety means a sugar moiety comprising at least one 2'- substituent group other than H or OH.
  • 3’ target site refers to the 3’-most nucleotide of a target nucleic acid which is complementary to an antisense oligonucleotide, when the antisense oligonucleotide is hybridized to the target nucleic acid.
  • 5’ target site refers to the 5’-most nucleotide of a target nucleic acid which is complementary to an antisense oligonucleotide, when the antisense oligonucleotide is hybridized to the target nucleic acid.
  • 5-methylcytosine means a cytosine modified with a methyl group attached to the 5 position.
  • a 5-methyl cytosine is a modified nucleobase.
  • abasic sugar moiety means a sugar moiety of a nucleoside that is not attached to a nucleobase.
  • bicyclic sugar or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms in the first ring thereby forming a bicyclic structure.
  • the first ring of the bicyclic sugar moiety is a furanosyl moiety.
  • the bicyclic sugar moiety does not comprise a furanosyl moiety.
  • non-bicyclic modified sugar moiety means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.
  • chirally enriched population means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers.
  • the molecules are modified oligonucleotides. In certain embodiments, the molecules are oligomeric compounds comprising modified oligonucleotides.
  • “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.
  • oligonucleotide in reference to an oligonucleotide means that is at least 70% of the nucleobases of the oligonucleotide and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions.
  • “Complementary region” in reference to a region of an oligonucleotide means that is at least 70% of the nucleobases of that region and the nucleobases of another nucleic acid or one or more regions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions, i.e. the nucleobase sequences are reverse complementary.
  • all references herein to an oligonucleotide e.g.
  • an antisense strand of a double-stranded oligonucleotide of the invention as complementary to a target sequence means that the nucleobase sequence of said oligonucleotide (e.g. the antisense strand of a double-stranded oligonucleotide of the invention) is reverse complementary to said target sequence.
  • Complementary nucleobases mean nucleobases that are capable of forming hydrogen bonds with one another.
  • Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G).
  • modified nucleobases that pair with natural nucleobases or with other modified nucleobases are known in the art and are not considered complementary nucleobases as defined herein unless indicated otherwise.
  • inosine can pair, but is not considered complementary, with adenosine, cytosine, or uracil.
  • Complementary oligonucleotides and/or nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated.
  • conjugate group means a group of atoms that is directly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.
  • conjugate linker means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.
  • conjugate moiety means a group of atoms that modifies one or more properties of a molecule compared to the identical molecule lacking the conjugate moiety, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance.
  • hotspot region is a range of nucleobases on a target nucleic acid that is amenable to oligomeric agent or oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.
  • internucleoside linkage is the covalent linkage between adjacent nucleosides in an oligonucleotide.
  • modified internucleoside linkage means any internucleoside linkage other than a phosphodiester internucleoside linkage.
  • linked nucleosides are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked).
  • linker-nucleoside means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.
  • mismatch or “non-complementary” means a nucleobase of a first nucleic acid sequence that is not complementary with the corresponding nucleobase of a second nucleic acid sequence or target nucleic acid when the first and second nucleic acid sequences are aligned.
  • motif means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.
  • modified nucleoside means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety.
  • nucleobase means an unmodified nucleobase or a modified nucleobase.
  • a nucleobase is a heterocyclic moiety.
  • an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G).
  • a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one other nucleobase.
  • a “5-methyl cytosine” is a modified nucleobase.
  • a universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases.
  • nucleobase sequence means the order of contiguous nucleobases in a nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.
  • an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and compounds having other modified nucleobases, such as “AT m CGAUCG,” wherein m C indicates a cytosine base comprising a methyl group at the 5-position.
  • nucleoside sequence refers only to the sequence of nucleobases in that SEQ ID NO.: X, independent of any sugar or internucleoside linkage modifications also described in such SEQ ID.
  • nucleoside means a compound or fragment of a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified.
  • oligomeric agent means a double-stranded oligonucleotide and optionally one or more additional features, such as a second oligonucleotide.
  • polynucleotide conjugate means a double-stranded oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group.
  • a double-stranded oligonucleotide comprises a first oligonucleotide strand that is paired with a second oligonucleotide strand that is complementary to the first oligonucleotide strand.
  • a double-stranded oligonucleotide comprises a sense oligonucleotide or strand (also known in the art as a passenger oligonucleotide or passenger strand), and an antisense oligonucleotide or strand (also known in the art as a guide oligonucleotide or guide strand).
  • sense oligonucleotide or strand also known in the art as a passenger oligonucleotide or passenger strand
  • an antisense oligonucleotide or strand also known in the art as a guide oligonucleotide or guide strand.
  • antisense activity means any detectable and/or measurable change attributable to the hybridization of an antisense strand to its target nucleic acid.
  • antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense strand.
  • antisense activity is the modulation of splicing of a target pre-mRNA.
  • antisense agent means an antisense strand and optionally one or more additional features, such as a sense strand.
  • additional features such as a sense strand.
  • a double-stranded oligonucleotide of the invention may be described as an antisense agent.
  • antisense compound means an antisense strand and optionally one or more additional features, such as a conjugate group.
  • An antisense agent may comprise an antisense compound and a sense strand.
  • sense compound means a sense strand and optionally one or more additional features, such as a conjugate group.
  • antisense oligonucleotide means an oligonucleotide, including the oligonucleotide portion of an antisense compound, that is capable of hybridizing to a target nucleic acid and is capable of at least one antisense activity.
  • Antisense oligonucleotides include but are not limited to antisense RNAi oligonucleotides and antisense RNase H oligonucleotides.
  • oligonucleotide or “sense strand” means an oligonucleotide, including the oligonucleotide portion of a sense compound, that is capable of hybridizing to an antisense oligonucleotide.
  • oligonucleotide means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified.
  • oligonucleotides consist of 8-50 linked nucleosides.
  • modified oligonucleotide means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified.
  • unmodified oligonucleotide means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.
  • stabilized phosphate group means a 5’-phosphate analog that is metabolically more stable than a 5’-phosphate as naturally occurs on DNA or RNA.
  • standard cell assay means the assays described in the Examples and reasonable variations thereof.
  • stereorandom chiral center in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration.
  • the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center.
  • the stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration.
  • a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.
  • sugar moiety means an unmodified sugar moiety or a modified sugar moiety.
  • unmodified sugar moiety means a 2’-OH(H) ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2’-H(H) deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”).
  • Unmodified sugar moieties have one hydrogen at each of the 1’, 3’, and 4’ positions, an oxygen at the 3’ position, and two hydrogens at the 5’ position.
  • modified sugar moiety or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.
  • sugar surrogate means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide.
  • Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.
  • target nucleic acid and “target RNA” mean a nucleic acid that an oligomeric compound is designed to affect.
  • Target RNA means an RNA transcript and includes pre-mRNA and mRNA unless otherwise specified.
  • target region means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.
  • terminal group means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.
  • cell-targeting moiety means a conjugate group or portion of a conjugate group that is capable of binding to a particular cell type or particular cell types.
  • hybridization means the annealing of oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.
  • complementary nucleic acid molecules include, but are not limited to, an antisense compound and a nucleic acid target. In certain embodiments, complementary nucleic acid molecules include, but are not limited to, an oligonucleotide and a nucleic acid target.
  • RNAi agent means an antisense agent that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid.
  • RNAi agents include, but are not limited to double-stranded siRNA, single-stranded RNAi (ssRNAi), and microRNA, including microRNA mimics.
  • RNAi agents may comprise conjugate groups and/or terminal groups.
  • an RNAi agent modulates the amount and/or activity, of a target nucleic acid.
  • the term RNAi agent excludes antisense agents that act through RNase H.
  • RNase H agent means an antisense agent that acts through RNase H to modulate a target nucleic acid and/or protein encoded by a target nucleic acid.
  • RNase H agents are single-stranded.
  • RNase H agents are double-stranded.
  • RNase H compounds may comprise conjugate groups and/or terminal groups.
  • an RNase H agent modulates the amount and/or activity of a target nucleic acid.
  • the term RNase H agent excludes antisense agents that act principally through RISC/Ago2.
  • reducing or “inhibiting” PSD3 means reducing expression of PSD3 RNA and/or protein levels in the presence of an oligomeric compound or oligomeric agent described herein compared to expression of PSD3 RNA and/or protein levels in the absence of an oligomeric compound or oligomeric agent described herein.
  • pharmaceutically acceptable carrier or diluent means any substance suitable for use in administering to an animal. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject.
  • a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.
  • pharmaceutically acceptable salts means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.
  • pharmaceutically acceptable may refer to salts, excipients, carriers, diluents, etc. approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia.
  • a pharmaceutical composition means a mixture of substances suitable for administering to a subject.
  • a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution.
  • a pharmaceutical composition shows activity in free uptake assay in certain cell lines.
  • prodrug means a therapeutic agent in a first form outside the body that is converted to a second form within an animal or cells thereof. Typically, conversion of a prodrug within the animal is facilitated by the action of an enzymes (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions. In certain embodiments, the first form of the prodrug is less active than the second form.
  • treating means improving a subject’s disease or condition by administering an oligomeric agent or oligomeric compound described herein.
  • treating a subject improves a symptom relative to the same symptom in the absence of the treatment.
  • treatment reduces in the severity or frequency of a symptom, or delays the onset of a symptom, slows the progression of a symptom, or slows the severity or frequency of a symptom.
  • therapeutically effective amount means an amount of a pharmaceutical agent or composition that has been observed to provide a therapeutic benefit to an animal. For example, a therapeutically effective amount may be observed to improve a symptom of a disease.
  • the terms “individual”, “subject”, and “patient”, are used interchangeably herein to refer to a mammalian subject for whom diagnosis, prognosis, disease monitoring, treatment, therapy, and/or therapy optimisation is desired.
  • the mammal can be (without limitation) a human, non-human primate, mouse, rat, dog, cat, horse, or cow.
  • the individual, subject, or patient is a human.
  • An “individual” may be an adult, juvenile or infant.
  • An “individual” may be male or female.
  • a "subject in need" of treatment for a particular condition can be an individual having that condition, diagnosed as having that condition, or at risk of developing that condition.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a condition in need of treatment or one or more complications or symptoms related to such a condition, and optionally, have already undergone treatment for a condition as defined herein or the one or more complications or symptoms related to said condition.
  • a subject can also be one who has not been previously diagnosed as having a condition as defined herein or one or more or symptoms or complications related to said condition.
  • a subject can be one who exhibits one or more risk factors for a condition, or one or more or symptoms or complications related to said condition or a subject who does not exhibit risk factors.
  • the term “healthy individual” refers to an individual or group of individuals who are in a healthy state, e.g., individuals who have not shown any symptoms of the disease, have not been diagnosed with the disease and/or are not likely to develop the disease e.g., a thrombotic event.
  • said healthy individual(s) is not on medication affecting haemostasis and has not been diagnosed with any other disease.
  • the one or more healthy individuals may have a similar sex, age, and/or body mass index (BMI) as compared with the test individual.
  • BMI body mass index
  • Application of standard statistical methods used in medicine permits determination of normal levels of expression in healthy individuals, and significant deviations from such normal levels.
  • control and “reference population” are used interchangeably.
  • the present inventors have surprisingly demonstrated that double-stranded oligonucleotides targeting a particular transcript for Pleckstrin and Sec7 Domain Containing 3 (PSD3) are capable of significantly reducing the amount or activity of PSD3 RNA in a cell. Accordingly, the present invention relates to double-stranded oligonucleotides which target said PSD3 transcript.
  • the target nucleic acid of the present invention is said PSD3 transcript, or a region or fragment thereof.
  • Contacting a cell with a double-stranded oligonucleotide which targets said PSD3 transcript typically reduce the amount of PSD3 RNA.
  • Said double-stranded oligonucleotide may be as described herein, and may be in the form of an isolated double-stranded oligonucleotides, or a polynucleotide conjugate, composition or and population comprising such a double-stranded oligonucleotide, as described herein.
  • the double-stranded oligonucleotides of the invention comprise an antisense strand (also known as a guide strand) which comprises a nucleobase sequence that is at least 80% complementary to an equal portion of said PSD3 transcript.
  • the double-stranded oligonucleotides of the invention comprise a sense strand (also known as a passenger strand) which comprises a nucleobase sequence that is at least 80% identical to an equal portion of said PSD3 transcript.
  • Said PSD3 transcript typically has the nucleic acid sequence set forth in SEQ ID NO: 1 (ENSEMBL Accession No. ENST00000327040.13, corresponding to GENBANK Accession No. NM_015310.4, both accessed 16 September 2023).
  • An exemplary human PSD3 protein sequence is set forth in UniProt Accession No. Q9NYI0 (version 2, accessed 17 September 2023).
  • the PSD3 transcript may have a nucleic acid sequence that is at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, a least 98%, at least 99%, at least 99.5%, at least 99.9% or more identical to SEQ ID NO: 1.
  • the PSD3 transcript may have a nucleic acid sequence that differs from SEQ ID NO: 1 by no more than 500, no more than 400, no more than 300, no more than 200, no more than 150, no more than 100, no more than 50, no more than 40, no more than 30, no more than 25, no more than 20, no more than 15, no more than 10, no more than 9, no more than 8, no more than 7, no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 nucleobase from SEQ ID NO: 1.
  • the PSD3 transcript of SEQ ID NO: 1 is 11,704 bps.
  • a double-stranded oligonucleotide of the invention may target any equal length portion of said transcript.
  • a double-stranded oligonucleotide of the invention may target a region of the PSD3 transcript corresponding to nucleobases 295 to 313 or nucleobases 7655 to 7673 of SEQ ID NO: 1.
  • the present inventors have identified hotspots within the PSD3 transcript of SEQ ID NO: 1.
  • double-stranded oligonucleotides targeting regions comprising or consisting of these hotspots, or fragments thereof may have increased antisense activity compared with double-stranded oligonucleotides targeting other regions of said PSD3 transcript.
  • double-stranded oligonucleotides targeting regions comprising or consisting of these hotspots, or fragments thereof may reduce the amount of PSD3 RNA and/or PSD3 protein by a greater amount than double-stranded oligonucleotides targeting regions outside these hotspots.
  • PSD3 hotspots may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 9000 of SEQ ID NO: 1, preferably from about nucleobase 1 to about nucleobase 8500 of SEQ ID NO: 1, more preferably from about nucleobase 1 to about nucleobase 8250 of SEQ ID NO: 1, even more preferably from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a PSD3 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a PSD3 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 700 of SEQ ID NO: 1, more preferably from about nucleobase 1 to about nucleobase 650 of SEQ ID NO: 1, even more preferably from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a PSD3 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a PSD3 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1000 to about nucleobase 4000 of SEQ ID NO: 1, more preferably from about nucleobase 1200 to about nucleobase 4000 of SEQ ID NO: 1, even more preferably from about nucleobase 1200 to about nucleobase 3750 of SEQ ID NO: 1, yet more preferably from about nucleobase 1200 to about nucleobase 3500 of SEQ ID NO: 1, even yet more preferably from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1.
  • a PSD3 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1.
  • a PSD3 hotspot may preferably comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 7000 to about nucleobase 9000 of SEQ ID NO: 1, more preferably from about nucleobase 7000 to about nucleobase 8500 of SEQ ID NO: 1, even more preferably from about nucleobase 7250 to about nucleobase 8500 of SEQ ID NO: 1, yet more preferably from about nucleobase 7250 to about nucleobase 8100 of SEQ ID NO: 1, even yet more preferably from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a PSD3 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a PSD3 hotspot may comprise or consist of a nucleobase sequence within a nucleobase sequence corresponding to: (i) from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • Double-stranded Oligonucleotides The present invention particularly relates to double-stranded oligonucleotides which target a PSD3 transcript or region thereof, particularly a PSD3 hotspot as defined herein.
  • the double-stranded oligonucleotides of the invention may consist essentially of RNA or DNA, preferably RNA.
  • the double-stranded oligonucleotide of the invention is an RNAi agent as defined herein, particularly an siRNA.
  • the double-stranded oligonucleotides of the invention, and particularly the antisense and sense strands of said double-stranded oligonucleotides comprise or consist of linked nucleosides.
  • Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides.
  • Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage. Certain modified nucleosides and modified internucleoside linkages suitable for use in modified oligonucleotides are described below.
  • the invention provides a double-stranded oligonucleotide comprising an antisense strand and a sense strand, wherein the antisense strand comprises a nucleobase sequence which comprises or consists of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion of a PSD3 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 8250 of SEQ ID NO: 1, even more preferably corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding from about nucleobase 1 to about nucleobase 700 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 650 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1000 to about nucleobase 4000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1200 to about nucleobase 4000 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1200 to about nucleobase 3750 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 1200 to about nucleobase 3500 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 1400 to about nucleobase 3500
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7000 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 7000 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 7250 to about nucleobase 8500 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 7250 to about nucleobase 8100 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 7500 to about nucleobase 8
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 90% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 95% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is at least 99% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand that is complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • the sense strand of a double-stranded oligonucleotide of the invention may comprise a nucleobase sequence which comprises or consists of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion of a PSD3 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 8250 of SEQ ID NO: 1, even more preferably corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 700 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 650 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1000 to about nucleobase 4000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1200 to about nucleobase 4000 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1200 to about nucleobase 3750 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 1200 to about nucleobase 3500 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 1400 to about nucleobase 3500 of
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7000 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 7000 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 7250 to about nucleobase 8500 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 7250 to about nucleobase 8100 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 7500 to about nucleobase 8100
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may a sense strand that is at least 90% identical to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may a sense strand that is at least 95% identical to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand that is at least 99% identical to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded oligonucleotide of the invention may a sense strand that is identical to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1.
  • a double-stranded nucleotide of the invention may comprise an antisense strand and a sense strand as defined herein.
  • the antisense strand and the sense strand are at least partially complementary to each other.
  • the antisense strand may be complementary to an equal length portion of a PSD3 nucleic acid as described herein, and the sense strand may be identical to the same equal length portion of the PSD3 nucleic acid, or identical to region which overlaps with said equal length portion.
  • Said overlap may be at least 5, at least 10, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23 or more nucleobases.
  • the invention provides a double-stranded oligonucleotide comprising an antisense strand and a sense strand, wherein: (i) the antisense strand comprises a nucleobase sequence which comprises or consists of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion of a PSD3 nucleic acid having the nucleobase sequence of SEQ ID NO: 1; and (ii) the sense strand comprises a nucleobase sequence which comprises or consists of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 8250 of SEQ ID NO: 1, even more preferably corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%,
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to the same equal length portion within a nu
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 700 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1 to about nucleobase 650 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least
  • a double- stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to the same equal length portion within a nu
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1000 to about nucleobase 4000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 1200 to about nucleobase 4000 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 1200 to about nucleobase 3750 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 1200 to about nucleobase 3500 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 1400 to about nucle
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to the same equal length portion within a
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7000 to about nucleobase 9000 of SEQ ID NO: 1, preferably corresponding to from about nucleobase 7000 to about nucleobase 8500 of SEQ ID NO: 1, more preferably corresponding to from about nucleobase 7250 to about nucleobase 8500 of SEQ ID NO: 1, yet more preferably corresponding to from about nucleobase 7250 to about nucleobase 8100 of SEQ ID NO: 1, even yet more preferably corresponding to from about nucleobase 7500 to about nu
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to the same equal length portion within a
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 80%, at least 85%, at least 90%, at least
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 90% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 90% identical to the same equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 95% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 95% identical to the same equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is at least 99% complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is at least 99% identical to the same equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand that is complementary to an equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucleobase 7500 to about nucleobase 8100 of SEQ ID NO: 1; and (ii) a sense strand that is identical to the same equal length portion within a nucleobase sequence corresponding to: from about nucleobase 1 to about nucleobase 8100 of SEQ ID NO: 1; from about nucleobase 1 to about nucleobase 600 of SEQ ID NO: 1; from about nucleobase 1400 to about nucleobase 3500 of SEQ ID NO: 1; or from about nucle
  • Exemplary unmodified nucleobase sequences for antisense (guide) strands of double-stranded oligonucleotides of the invention are given in column 4 of Table 1, with the corresponding sequence identifier in column 5.
  • the compound number is shown in column 1.
  • the position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is complementary to a given antisense nucleobase sequence is given in column 2.
  • the position of the right-most (3'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is complementary to a given antisense nucleobase sequence is given in column 3.
  • Exemplary modified nucleobase sequences for antisense (guide) strands of double-stranded oligonucleotides of the invention are given in column 2 of Table 3, with the corresponding sequence identifier in column 3. The compound number is shown in column 1.
  • Preferred exemplary unmodified nucleobase sequences for antisense (guide) strands of double-stranded oligonucleotides of the invention are given in column 4 of Table 2, with the corresponding sequence identifier in column 5.
  • the compound number is shown in column 1.
  • the position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is complementary to a given antisense nucleobase sequence is given in column 2.
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 23
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 18
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 3
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274, 12
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151,
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294,
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283,
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 80
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142
  • the antisense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, or at least 23 contiguous nucleobases, particularly 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 11
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 18
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 3
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339,
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863,
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274, 12
  • the antisense strand may have a nucleobase sequence comprising 19, 20, 21, 22 or 23 contiguous nucleobases of any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271,
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 182, 183
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 36
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339, 343, 3
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863, 866, 8
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274, 1278, 12
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271, 1275,
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 2, 3, 6, 7, 10, 11, 14, 15, 18, 19, 22, 23, 26, 27, 30, 31, 34, 35, 38, 39, 42, 43, 46, 47, 50, 51, 54, 55, 58, 59, 62, 63, 66, 67, 70, 71, 74, 75, 78, 79, 82, 83, 86, 87, 90, 91, 94, 95, 98, 99, 102, 103, 106, 107, 110, 111, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131, 134, 135, 138, 139, 142, 143, 146, 147, 150, 151, 154, 155, 158, 159, 162, 163, 166, 167, 170, 171, 174, 175, 178, 179, 182, 183,
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102, 106, 110, 114, 118, 122, 126, 130, 134, 138, 142, 146, 150, 154, 158, 162, 166, 170, 174, 178, 182, 186, 190, 194, 198, 202, 206, 210, 214, 218, 222, 226, 230, 234, 238, 242, 246, 250, 254, 258, 262, 266, 270, 274, 278, 282, 286, 290, 294, 298, 302, 306, 310, 314, 318, 322, 326, 330, 334, 338, 342, 346, 350, 354, 358, 362, 3
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91, 95, 99, 103, 107, 111, 115, 119, 123, 127, 131, 135, 139, 143, 147, 151, 155, 159, 163, 167, 171, 175, 179, 183, 187, 191, 195, 199, 203, 207, 211, 215, 219, 223, 227, 231, 235, 239, 243, 247, 251, 255, 259, 263, 267, 271, 275, 279, 283, 287, 291, 295, 299, 303, 307, 311, 315, 319, 323, 327, 331, 335, 339, 343, 347,
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 34, 35, 54, 55, 58, 59, 142, 143, 158, 159, 250, 251, 262, 263, 282, 283, 286, 287, 390, 391, 398, 399, 426, 427, 470, 471, 478, 479, 494, 495, 502, 503, 522, 523, 566, 567, 574, 575, 586, 587, 606, 607, 618, 619, 626, 627, 654, 655, 666, 667, 678, 679, 694, 695, 698, 699, 722, 723, 730, 731, 742, 743, 778, 779, 802, 803, 822, 823, 830, 831, 842, 843, 846, 847, 858, 859, 862, 863, 866, 867,
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 34, 54, 58, 142, 158, 250, 262, 282, 286, 390, 398, 426, 470, 478, 494, 502, 522, 566, 574, 586, 606, 618, 626, 654, 666, 678, 694, 698, 722, 730, 742, 778, 802, 822, 830, 842, 846, 858, 862, 866, 870, 874, 878, 886, 906, 914, 946, 954, 970, 978, 1006, 1018, 1022, 1026, 1034, 1038, 1042, 1058, 1082, 1086, 1102, 1118, 1126, 1142, 1146, 1150, 1154, 1158, 1182, 1186, 1190, 1210, 1214, 1254, 1270, 1274, 1278, 1282,
  • the nucleobase sequence of the antisense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 35, 55, 59, 143, 159, 251, 263, 283, 287, 391, 399, 427, 471, 479, 495, 503, 523, 567, 575, 587, 607, 619, 627, 655, 667, 679, 695, 699, 723, 731, 743, 779, 803, 823, 831, 843, 847, 859, 863, 867, 871, 875, 879, 887, 907, 915, 947, 955, 971, 979, 1007, 1019, 1023, 1027, 1035, 1039, 1043, 1059, 1083, 1087, 1103, 1119, 1127, 1143, 1147, 1151, 1155, 1159, 1183, 1187, 1191, 1211, 1215, 1255, 1271, 1275, 1279
  • Exemplary unmodified nucleobase sequences for sense (passenger) strands of double-stranded oligonucleotides of the invention are given in column 6 of Table 1, with the corresponding sequence identifier in column 7.
  • the compound number is shown in column 1.
  • the position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is identical to a given sense nucleobase sequence is given in column 2.
  • the position of the right-most (3'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is identical to a given sense nucleobase sequence is given in column 3.
  • Exemplary modified nucleobase sequences for sense (passenger) strands of double-stranded oligonucleotides of the invention are given in column 4 of Table 3, with the corresponding sequence identifier in column 5. The compound number is shown in column 1.
  • Preferred exemplary unmodified nucleobase sequences for sense (passenger) strands of double-stranded oligonucleotides of the invention are given in column 6 of Table 2, with the corresponding sequence identifier in column 7.
  • the compound number is shown in column 1.
  • the position of the left-most (5'-most) residue of the corresponding nucleobase sequence in the PSD3 transcript of SEQ ID NO: 1 which is identical to a given sense nucleobase sequence is given in column 2.
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 10
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9%, or more, up to 100% identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869, 8
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284, 12
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 90% identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273, 12
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 35
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 3
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 95% identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 35
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 3
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is at least 99% identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 31
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160,
  • the sense strand may have a nucleobase sequence comprising at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 or at least 21 contiguous nucleobases, particularly 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149,
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184, 185,
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, 360,
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 3
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869, 872,
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284, 1296,
  • the sense strand may have a nucleobase sequence comprising 19, 20 or 21 contiguous nucleobases of any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273, 1277,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184, 185,
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, 360, 36
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869, 872, 8
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284, 1296, 1
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273, 1277, 1281
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 4, 5, 8, 9, 12, 13, 16, 17, 20, 21, 24, 25, 28, 29, 32, 33, 36, 37, 40, 41, 44, 45, 48, 49, 52, 53, 56, 57, 60, 61, 64, 65, 68, 69, 72, 73, 76, 77, 80, 81, 84, 85, 88, 89, 92, 93, 96, 97, 100, 101, 104, 105, 108, 109, 112, 113, 116, 117, 120, 121, 124, 125, 128, 129, 132, 133, 136, 137, 140, 141, 144, 145, 148, 149, 152, 153, 156, 157, 160, 161, 164, 165, 168, 169, 172, 173, 176, 177, 180, 181, 184, 185, 188,
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92, 96, 100, 104, 108, 112, 116, 120, 124, 128, 132, 136, 140, 144, 148, 152, 156, 160, 164, 168, 172, 176, 180, 184, 188, 192, 196, 200, 204, 208, 212, 216, 220, 224, 228, 232, 236, 240, 244, 248, 252, 256, 260, 264, 268, 272, 276, 280, 284, 288, 292, 296, 300, 304, 308, 312, 316, 320, 324, 328, 332, 336, 340, 344, 348, 352, 356, 360, 364, 3
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, 93, 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, 145, 149, 153, 157, 161, 165, 169, 173, 177, 181, 185, 189, 193, 197, 201, 205, 209, 213, 217, 221, 225, 229, 233, 237, 241, 245, 249, 253, 257, 261, 265, 269, 273, 277, 281, 285, 289, 293, 297, 301, 305, 309, 313, 317, 321, 325, 329, 333, 337, 341, 345, 349, 35
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 36, 37, 56, 57, 60, 61, 144, 145, 160, 161, 252, 253, 264, 265, 284, 285, 288, 289, 392, 393, 400, 401, 428, 429, 472, 473, 480, 481, 496, 497, 504, 505, 524, 525, 568, 569, 576, 577, 588, 589, 608, 609, 620, 621, 628, 629, 656, 657, 668, 669, 680, 681, 696, 697, 700, 701, 724, 725, 732, 733, 744, 745, 780, 781, 804, 805, 824, 825, 832, 833, 844, 845, 848, 849, 860, 861, 864, 865, 868, 869, 872, 873,
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that is identical to any of SEQ ID NOs: 36, 56, 60, 144, 160, 252, 264, 284, 288, 392, 400, 428, 472, 480, 496, 504, 524, 568, 576, 588, 608, 620, 628, 656, 668, 680, 696, 700, 724, 732, 744, 780, 804, 824, 832, 844, 848, 860, 864, 868, 872, 876, 880, 888, 908, 916, 948, 956, 972, 980, 1008, 1020, 1024, 1028, 1036, 1040, 1044, 1060, 1084, 1088, 1104, 1120, 1128, 1144, 1148, 1152, 1156, 1160, 1184, 1188, 1192, 1212, 1216, 1256, 1272, 1276, 1280, 1284, 1296, 1300,
  • the nucleobase sequence of the sense strand may consist of a nucleobase sequence that identical to any of SEQ ID NOs: 37, 57, 61, 145, 161, 253, 265, 285, 289, 393, 401, 429, 473, 481, 497, 505, 525, 569, 577, 589, 609, 621, 629, 657, 669, 681, 697, 701, 725, 733, 745, 781, 805, 825, 833, 845, 849, 861, 865, 869, 873, 877, 881, 889, 909, 917, 949, 957, 973, 981, 1009, 1021, 1025, 1029, 1037, 1041, 1045, 1061, 1085, 1089, 1105, 1121, 1129, 1145, 1149, 1153, 1157, 1161, 1185, 1189, 1193, 1213, 1217, 1257, 1273, 1277, 1281, 12
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 2+4; 6+8; 10+12; 14+16; 18+20; 22+24; 26+28; 30+32; 34+36; 38+40; 42+44; 46+48; 50+52; 54+56; 58+60; 62+64; 66+68; 70+72; 74+76; 78+80; 82+84; 86+88; 90+92; 94+96; 98+100; 102+104; 106+108; 110+112; 114+116; 118+120; 122+124; 126+128; 130+132; 134+136; 138+140
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 3+5; 7+9; 11+13; 15+17; 19+21; 23+25; 27+29; 31+33; 35+37; 39+41; 43+45; 47+49; 51+53; 55+57; 59+61; 63+65; 67+69; 71+73; 75+77; 79+81; 83+85; 87+89; 91+93; 95+97; 99+101; 103+105; 107+109; 111+113; 115+117; 119+121; 123+125; 127+129; 131+133; 135+137; 139+
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 34+36; 54+56; 58+60; 142+144; 158+160; 250+252; 262+264; 282+284; 286+288; 390+392; 398+400; 426+428; 470+472; 478+480; 494+496; 502+504; 522+524; 566+568; 574+576; 586+588; 606+608; 618+620; 626+628; 654+656; 666+668; 678+680; 694+696; 698+700; 7
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 35+37; 55+57; 59+61; 143+145; 159+161; 251+253; 263+265; 283+285; 287+289; 391+393; 399+401; 427+429; 471+473; 479+481; 495+497; 503+505; 523+525; 567+569; 575+577; 587+589; 607+609; 619+621; 627+629; 655+657; 667+669; 679+681; 695+697; 699
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any compound as shown in any one of Tables 1-6.
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any compound as shown in any one of Tables 2, 4 or 6.
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any compound as shown in any one of Tables 1 or 2.
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any compound as shown in Table 2.
  • a double-stranded oligonucleotide of the invention an antisense strand and a sense strand of any compound as shown in any one of Tables 3 or 4.
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any compound as shown in Table 4. It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target RNA in an oocyte injection model.
  • Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target RNA, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.
  • antisense and/or sense strands can have any of a variety of ranges of lengths.
  • oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range.
  • X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X ⁇ Y.
  • oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16
  • a double-stranded oligonucleotide of the invention may comprise an antisense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may comprise a sense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides, more preferably of between 19 to 21 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides, more
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 19 to 23 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 19 to 21 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 10 to 25, 10 to 30, 12 to 25, 13 to 25, 14 to 25, 15 to 25, 16 to 25, 17 to 25, 18 to 25, 19 to 25, 20 to 25, 21 to 25, 22 to 25, 23 to 25, 19 to 24, 20 to 24, 21 to 24, 22 to 24, 19 to 23, 20 to 23, 21 to 23, 19 to 22, 20 to 22 or 19 to 21 linked nucleosides, preferably of between 19 to 23 linked nucleosides, more preferably of between 19 to 21 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 19 to 23 linked nucleosides. More preferably a double-stranded oligonucleotide of the invention may comprise: (i) an antisense strand with a nucleobase sequence that consists of between 19 to 23 linked nucleosides; and (ii) a sense strand with a nucleobase sequence that consists of between 19 to 21 linked nucleosides.
  • a double-stranded oligonucleotide of the invention may be blunt-ended.
  • the antisense strand and sense strand may be the same length and hybridise such that the 5’-most nucleobase of the antisense strand hybridises with the 3’-most nucleobase of the sense strand, and the 3’-most nucleobase of the antisense strand hybridises with the 5’-most nucleobase of the sense strand.
  • a double-stranded oligonucleotide of the invention may have a 3’ and/or 5’ overhang on the antisense strand.
  • a double-stranded oligonucleotide of the invention may have a 3’ overhang on the antisense strand.
  • the antisense strand and sense strands hybridise such that one or more nucleobase at the 3’ end of the antisense strand extends beyond the 5’-most base of the sense strand.
  • the one or more nucleobase at the 3’ end of the antisense strand that extend beyond the 5’- most base of the sense strand do not hybridise with the sense strand.
  • the 3’ overhang on the sense strand may be from between about 0 nucleobases (i.e. zero overhang) to about 6 nucleobases.
  • the 3’ overhang on the sense strand may be from between about 0 nucleobases (i.e. zero overhang) to about 5 nucleobases.
  • the 3’ overhang on the sense strand may be 0, 1, 2, 3, 4, 5 or 6 nucleobases.
  • the 3’ overhang on the sense strand may be from between about 2 nucleobases to about 5 nucleobases, such as 2, 3, 4 or 5 nucleobases.
  • Modified nucleosides may comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase. Modified nucleosides comprising the following modified sugar moieties and/or the following modified nucleobases may be incorporated into the antisense strand and/or sense strand of a double-stranded oligonucleotide of the invention. An oligonucleotide comprising one or more modified nucleoside may be referred to as a modified oligonucleotide.
  • an antisense strand and/or sense strand of a double-stranded oligonucleotide of the invention comprising one or more modified nucleotide may be referred to as a modified oligonucleotide, particularly a modified antisense and/or sense strand respectively.
  • a double- stranded oligonucleotide comprising such a modified antisense and/or sense strand may itself be referred to as a modified oligonucleotide, particularly a modified double-stranded oligonucleotide.
  • Modified Sugars In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties.
  • modified sugar moieties are bicyclic or tricyclic sugar moieties.
  • modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.
  • at least one nucleoside of the antisense strand and/or the sense strand may comprise a modified sugar moiety.
  • modified sugar moieties include, but are not limited to, a non-bicyclic sugar moiety, such as a 2’-MOE sugar moiety, a 2’-F sugar moiety, a 2’-OMe sugar moiety, or a 2’-NMA sugar moiety, or a bicyclic sugar moiety, such as a 2’-4’ bridge selected from –O-CH2-; and –O-CH(CH3)-. Modification of at least one nucleoside of the sense strand and/or the antisense by a non-bicyclic sugar moiety may be preferred.
  • a non-bicyclic sugar moiety such as a 2’-MOE sugar moiety, a 2’-F sugar moiety, a 2’-OMe sugar moiety, or a 2’-NMA sugar moiety
  • a bicyclic sugar moiety such as a 2’-4’ bridge selected from –O-CH2-; and –O-CH(CH3)-. Modification of at least one nucleo
  • At least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or more, up to 100% 80%, at least 90%, or 100% of the nucleosides of the antisense strand and/or the sense strand comprises a modified sugar moiety selected from 2’-F and 2’-OMe.
  • at least one nucleoside of the antisense strand and/or the sense strand may comprise a sugar surrogate.
  • Suitable sugar surrogates include, but are not limited to, morpholino, peptide nucleic acid (PNA), glycol nucleic acid (GNA), and unlocked nucleic acid (UNA).
  • PNA peptide nucleic acid
  • GNA glycol nucleic acid
  • UNA unlocked nucleic acid
  • at least one nucleoside of the antisense strand comprises a sugar surrogate, which can be a GNA.
  • at least one nucleoside of the antisense strand and/or the sense strand, particularly the antisense strand may comprise a xeno nucleic acid (XNA).
  • one or more nucleobase within the antisense and/or sense strand of a double-stranded oligonucleotide of the invention may have with a backbone constructed from sugars that are distinct from the natural ribose sugars found in RNA.
  • Inclusion of one or more XNA may improve the off-target profile of the double-stranded oligonucleotide, i.e. may decrease off-target binding.
  • XNA X-locked nucleic acids
  • GAA glycol nucleic acids
  • DNA DNA
  • 2'-deoxy-2'-fluoro-arabinonucleic acids (2’F- ANA)
  • threose nucleic acids TAA
  • SNA serinol nucleic acids
  • FNA flexible nucleic acids
  • 2’NH2-RNA, 1’,2’-seco-DNA 3(S),5-dihydroxypentyl nucleic acids
  • THP six-membered tetrahydropyran
  • the XNA is a GNA, UNA or DNA.
  • any one of positions 6, 7 and 8 may be an XNA, which may be independently selected from any XNA, including those identified herein.
  • the antisense strand may comprise an XNA at position 6.
  • the antisense strand may comprise an XNA at position 7.
  • the antisense strand may comprise an XNA at position 8.
  • the antisense strand may comprise an XNA at positions 6 and 7.
  • the antisense strand may comprise an XNA at positions 6 and 8.
  • the antisense strand may comprise an XNA at positions 7 and 8.
  • the antisense strand may comprise an XNA at positions 6, 7 and 8.
  • the antisense strand may comprise an XNA at position 7.
  • an antisense strand may have a GNA, UNA or DNA at one or more of positions 6, 7 and/or 8, preferably at least position 7 is a GNA, UNA or DNA.
  • modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure.
  • non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2’, 3’, 4’, and/or 5’ positions.
  • one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched.
  • 2’-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2’-F, 2'-OCH 3 (“OMe” or “O-methyl”), and 2'-O(CH2)2OCH3 (“MOE” or “O-methoxyethyl”).
  • non-bicyclic modified sugar moieties comprise a substituent group at the 3’-position.
  • substituent groups suitable for the 3’-position of modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl (e.g., methyl, ethyl).
  • non-bicyclic modified sugar moieties comprise a substituent group at the 4’-position.
  • 4’-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128.
  • non-bicyclic modified sugar moieties examples include but are not limited to: 5’-methyl (R or S), 5'-vinyl, ethyl, and 5’-methoxy.
  • non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2'-F-5'-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836).
  • a non-bridging 2’-substituent group selected from: F, NH2, N3, OCF3, OCH3, O(CH
  • a non-bridging 2’-substituent group selected from: F, OCF 3, OCH 3 , OCH 2 CH 2 OCH 3 , O(CH 2 ) 2 SCH 3 , O(CH 2 ) 2 ON(CH 3 ) 2 , O(CH 2 ) 2 O(CH 2
  • a 2’-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2’-substituent group selected from: F, OCH 3 , and OCH 2 CH 2 OCH 3 .
  • a 3’-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 3’-substituent group that is OCH2CH2OCH3.
  • modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by isomeric configuration.
  • a 2’-deoxyfuranosyl sugar moiety may be in seven isomeric configurations other than the naturally occurring ⁇ -D-deoxyribosyl configuration.
  • modified sugar moieties are described in, e.g., WO 2019/157531, incorporated by reference herein.
  • a 2’-modified sugar moiety has an additional stereocenter at the 2’-position relative to a 2’-deoxyfuranosyl sugar moiety; therefore, such sugar moieties have a total of sixteen possible isomeric configurations.
  • 2’-modified sugar moieties described herein are in the ⁇ -D-ribosyl isomeric configuration unless otherwise specified. In naturally occurring nucleic acids, sugars are linked to one another 3’ to 5’.
  • oligonucleotides include one or more nucleoside or sugar moiety linked at an alternative position, for example at the 2’ or inverted 5’ to 3’.
  • modified sugar moieties are sugar surrogates.
  • the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom.
  • such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein.
  • sugar surrogates comprise a 4’-sulfur atom and a substitution at the 2'- position (see, e.g., Bhat et al., U.S.7,875,733 and Bhat et al., U.S.7,939,677) and/or the 5’ position.
  • sugar surrogates comprise rings having other than 5 atoms.
  • a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted.
  • Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), arabinonucleic acid (“ANA”), mannitol nucleic acid (“MNA”) (see, e.g., Leumann, CJ. Bioorg. & Med. Chem.2002, 10, 841-854), fluoro HNA: (“F-HNA”, see e.g.
  • F-HNA can also be referred to as a F-THP or 3'-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula: wherein, independently, for each of said modified THP nucleoside: Bx is a nucleobase moiety; T 3 and T 4 are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T 3 and T 4 is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T3 and T4 is H, a hydroxyl protecting group
  • modified THP nucleosides are provided wherein q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 are each H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is other than H. In certain embodiments, at least one of q 1 , q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R1 and R2 is F.
  • sugar surrogates comprise acyclic moieties.
  • nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol.
  • nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876 are described in Manoharan et al., WO2011/133876.
  • Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Patent Nos. 5,539,082; 5,714,331; and 5,719,262. Additional PNA compounds suitable for use in the oligonucleotides of the invention are described in, for example, in Nielsen et al., Science, 1991, 254, 1497-1500.
  • sugar surrogates are the “unlocked” sugar structure of UNA (unlocked nucleic acid) nucleosides.
  • UNA is an unlocked acyclic nucleic acid, wherein any of the bonds of the sugar has been removed, forming an unlocked sugar surrogate.
  • Representative U.S. publications that teach the preparation of UNA include, but are not limited to, US Patent No. 8,314,227; and US Patent Publication Nos. 2013/0096289; 2013/0011922; and 2011/0313020, the entire contents of each of which are hereby incorporated herein by reference.
  • sugar surrogates are the glycerol as found in GNA (glycol nucleic acid) nucleosides as depicted below: (S)-GNA where Bx represents any nucleobase.
  • the XNA may be a 2'-deoxy-2'-fluoro-arabinonucleic acid (2’F-ANA) as depicted below:
  • the XNA may be a threose nucleic acid (TNA) as depicted below: where B represents any nucleobase.
  • the XNA may be a serinol nucleic acid (SNA) as depicted below:
  • the XNA may be a flexible nucleic acid (FNA) as depicted below: where B represents any nucleobase.
  • the XNA may be a 2’NH2-RNA as depicted below: where B represents any nucleobase.
  • the XNA may be a 3(S),5-dihydroxypentyl nucleoside as depicted below: where Base represents any nucleobase. In certain embodiments, the XNA may be a 1’,2’-seco-DNA as depicted below: where Base represents any nucleobase. Many other non-bicyclic, bicyclic and tricyclic sugar and sugar surrogates are known in the art that can be used in modified nucleosides. Modified Internucleoside Linkages The naturally occurring internucleoside linkage of RNA and DNA is a 3' to 5' phosphodiester linkage. Nucleosides of modified oligonucleotides (e.g.
  • a modified antisense and/or sense strand of the invention may be linked together using one or more modified internucleoside linkages.
  • the two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom.
  • Modified internucleoside linkages compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide.
  • internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non- phosphorous-containing internucleoside linkages are well known to those skilled in the art. In certain embodiments, a modified internucleoside linkage is any of those described in WO/2021/030778, incorporated by reference herein.
  • a modified internucleoside linkage comprises a mesyl phosphoramidate linking group having a formula:
  • a mesyl phosphoramidate internucleoside linkage may comprise a chiral center.
  • modified oligonucleotides comprising (Rp) and/or (Sp) mesyl phosphoramidates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:
  • Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates, mesyl phosphoramidates, and phosphorothioates. Modified oligonucleotides (e.g.
  • modified antisense and/or sense strands of the invention and/or modified double-stranded oligonucleotides comprising such modified antisense and/or sense strands) comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides (particularly modified double-stranded oligonucleotides) comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate or other linkages containing chiral centers in particular stereochemical configurations.
  • populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages in the antisense and/or sense strand, particularly both the antisense and sense strands, are stereorandom.
  • populations of modified oligonucleotides comprise mesyl phosphoramidate internucleoside linkages wherein all of the mesyl phosphoramidate internucleoside linkages in the antisense and/or sense strand, particularly both the antisense and sense strands, are stereorandom.
  • modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate or mesyl phosphoramidate linkage. Nonetheless, each individual phosphorothioate or mesyl phosphoramidate of each individual oligonucleotide molecule has a defined stereoconfiguration.
  • populations of modified oligonucleotides are enriched for modified oligonucleotides (particularly modified double-stranded oligonucleotides) comprising one or more particular phosphorothioate or mesyl phosphoramidate internucleoside linkages in the antisense and/or sense strand in a particular, independently selected stereochemical configuration.
  • the particular configuration of the particular phosphorothioate or mesyl phosphoramidate linkage is present in at least 65% of the molecules in the population.
  • the particular configuration of the particular phosphorothioate or mesyl phosphoramidate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate or mesyl phosphoramidate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate or mesyl phosphoramidate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate or mesyl phosphoramidate linkage is present in at least 99% of the molecules in the population.
  • Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555.
  • a population of modified oligonucleotides is enriched for modified oligonucleotides (particularly modified double-stranded oligonucleotides) having at least one indicated phosphorothioate or mesyl phosphoramidate in the (Sp) configuration.
  • a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate or mesyl phosphoramidate in the antisense and/or sense strand in the (Rp) configuration.
  • modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase: Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides (particularly modified double-stranded oligonucleotides) described herein can be stereorandom or in a particular stereochemical configuration.
  • Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y.S. Sanghvi and P.D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH 2 component parts. In certain embodiments, modified oligonucleotides (e.g.,
  • modified antisense and/or sense strands of the invention and/or modified double-stranded oligonucleotides comprising such modified antisense and/or sense strands
  • an inverted nucleoside is terminal (i.e., the last nucleoside on one end of an oligonucleotide) and so only one internucleoside linkage depicted above will be present.
  • additional features such as a conjugate group may be attached to the inverted nucleoside.
  • terminal inverted nucleosides can be attached to either or both ends of an oligonucleotide.
  • such groups lack a nucleobase and are referred to herein as inverted sugar moieties.
  • an inverted sugar moiety is terminal (i.e., attached to the last nucleoside on one end of an oligonucleotide) and so only one internucleoside linkage above will be present.
  • additional features such as a conjugate group
  • Such terminal inverted sugar moieties can be attached to either or both ends of an oligonucleotide.
  • nucleic acids can be linked 2’ to 5’ rather than the standard 3’ to 5’ linkage. Such a linkage is illustrated below. , wherein each Bx represents any nucleobase.
  • at least one internucleoside linkage of the antisense strand and/or the sense strand may comprise a modified internucleoside linkage.
  • modified internucleoside linkages include phosphorothioate internucleoside linkages.
  • At least one of the first, second, or third internucleoside linkages from the 5’ end and/or the 3’ end of the antisense strand oligonucleotide comprises a phosphorothioate linkage.
  • the two 5’ most internucleoside linkages in the antisense strand are phosphorothioate internucleoside linkages and/or the two 3’ most internucleoside linkages of the antisense strand are phosphorothioate internucleoside linkages.
  • the two 5’ most internucleoside linkages in the antisense strand are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of the antisense strand are phosphorothioate internucleoside linkages.
  • at least one of the first, second, or third internucleoside linkages from the 5’ end and/or the 3’ end of the sense strand comprises a phosphorothioate linkage.
  • the two 5’ most internucleoside linkages in the sense strand are phosphorothioate internucleoside linkages and/or the two 3’ most internucleoside linkages of the sense strand are phosphorothioate internucleoside linkages.
  • the two 5’ most internucleoside linkages in the sense strand are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages of the sense strand are phosphorothioate internucleoside linkages.
  • At least one of the first, second, or third internucleoside linkages from the 5’ end and/or the 3’ end of the antisense strand oligonucleotide comprises a phosphorothioate linkage
  • at least one of the first, second, or third internucleoside linkages from the 5’ end and/or the 3’ end of the sense strand comprises a phosphorothioate linkage
  • the two 5’ most internucleoside linkages in the antisense strand are phosphorothioate internucleoside linkages
  • the two 3’ most internucleoside linkages of the antisense strand are phosphorothioate internucleoside linkages
  • the two 5’ most internucleoside linkages in the sense strand are phosphorothioate internucleoside linkages
  • the two 3’ most internucleoside linkages of the sense strand are phosphorothioate internucleoside linkages.
  • At least one internucleoside linkage of the antisense strand and/or the sense strand can comprise a phosphodiester internucleoside linkage.
  • each internucleoside linkage of the sense antisense strand and/or the sense strand can be independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.
  • Modified Bases In any of the double-stranded oligonucleotides described herein, at least one nucleobase of the antisense strand and/or the sense strand can be modified nucleobase.
  • Said modified nucleobase may be 5-methylcytosine or methyl-uracil.
  • An antisense and/or sense strand may each independently comprise one or more nucleosides comprising an unmodified nucleobase.
  • An antisense and/or sense strand may each independently comprise one or more nucleosides comprising a modified nucleobase.
  • An antisense and/or sense strand may each independently comprise one or more nucleosides that does not comprise a nucleobase, referred to as an abasic nucleoside.
  • An antisense and/or sense strand may each independently comprise one or more inosine nucleosides (i.e., nucleosides comprising a hypoxanthine nucleobase).
  • Modified nucleobases may be selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and O-6 substituted purines.
  • modified nucleobases are selected from: 5-methylcytosine, 2-aminopropyladenine, 5- hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2- propyladenine , 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (-C ⁇ C-CH3) uracil, 5- propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5- trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguaguanine
  • nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3- diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp).
  • Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7- deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
  • Further nucleobases include those disclosed in Merigan et al., U.S.
  • the antisense strand may comprise a stabilized phosphate group attached to the 5’ position of the 5’-most nucleoside.
  • the stabilized phosphate group comprises a cyclopropyl phosphonate or 5-vinylphosphonate (also referred to as an (E)-vinyl phosphonate).
  • a double-stranded oligonucleotide may comprise one or more terminal groups.
  • a double- stranded oligonucleotide may comprise a stabilized 5’-phosphate on the antisense and/or sense strand, particularly the antisense strand.
  • Stabilized 5’-phosphates include, but are not limited to 5’-phosphonates, including, but not limited to 5’-vinylphosphonates.
  • terminal groups comprise one or more abasic sugar moieties and/or inverted nucleosides.
  • terminal groups comprise one or more 2’-linked nucleosides or sugar moieties.
  • the 2’-linked group is an abasic sugar moiety.
  • a double stranded oligonucleotide of the invention may comprise one or more modified nucleosides comprising a modified sugar moiety in the antisense strand and/or the sense strand.
  • a double stranded oligonucleotide of the invention may comprise one or more modified nucleosides comprising a modified nucleobase in the antisense strand and/or the sense strand.
  • a double stranded oligonucleotide of the invention may comprise one or more modified internucleoside linkage in the antisense strand and/or the sense strand.
  • the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a double stranded oligonucleotide of the invention may define a pattern or motif.
  • the patterns of sugar moieties, nucleobases, and internucleoside linkages may be each independent of one another.
  • the patterns of sugar moieties in the antisense and sense strand may be independent of each other.
  • the patterns of nucleobases in the antisense and sense strand may be independent of each other.
  • the patterns of internucleoside linkages in the antisense and sense strand may be independent of each other.
  • the antisense strand of a double stranded oligonucleotide of the invention may comprise may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).
  • nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases.
  • the sense strand of a double stranded oligonucleotide of the invention may comprise may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).
  • a double stranded oligonucleotide of the invention may comprise may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).
  • nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases.
  • a double stranded oligonucleotide of the invention may comprise may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif of its antisense strand and/or sense strand (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).
  • the antisense and/or sense strand of a double-stranded oligonucleotides may comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the antisense and/or sense strand or region thereof in a defined pattern or sugar motif.
  • sugar motifs include but are not limited to any of the sugar modifications discussed herein.
  • the antisense and/or sense strand of a double-stranded oligonucleotides may comprise modified and/or unmodified nucleobases arranged along the antisense and/or sense strand or region thereof in a defined pattern or motif.
  • each nucleobase is modified.
  • none of the nucleobases are modified.
  • each purine or each pyrimidine is modified.
  • each adenine is modified.
  • each guanine is modified.
  • each thymine is modified.
  • each uracil is modified.
  • each cytosine is modified.
  • some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines.
  • all of the cytosine nucleobases are 5- methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.
  • a modified antisense and/or sense strand may comprise a block of modified nucleobases.
  • the block is at the 3’-end of the antisense and/or sense strand. In certain embodiments the block is within 3 nucleosides of the 3’-end of the antisense and/or sense strand. In certain embodiments, the block is at the 5’-end of the antisense and/or sense strand. In certain embodiments the block is within 3 nucleosides of the 5’-end of the antisense and/or sense strand.
  • the antisense and/or sense strand of a double-stranded oligonucleotides may comprise modified and/or unmodified internucleoside linkages arranged along the antisense and/or sense strand or region thereof in a defined pattern or motif.
  • each internucleoside linkage of an antisense and/or sense strand is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage.
  • each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, a (Sp) phosphorothioate, and a (Rp) phosphorothioate.
  • all of the phosphorothioate linkages in the antisense and/or sense strand are stereorandom.
  • the antisense and/or sense strand of a double-stranded oligonucleotide may comprise at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
  • Said antisense and/or sense strand of a double-stranded oligonucleotide may comprise at least one particular phosphorothioate internucleoside linkage having the (Sp) or (Rp) configuration, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • the antisense and/or sense strand of a double- stranded oligonucleotide may comprise the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.
  • the antisense and/or sense strand of a double-stranded oligonucleotides may have at least 2 (e.g. at least 3) contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5’ to 3’ direction.
  • modified oligonucleotide which is the antisense or sense strand of a double-stranded oligonucleotide of the invention.
  • modified oligonucleotides e.g. a modified antisense and/or sense strand, or a double-stranded oligonucleotide comprises such an antisense and/or sense strand
  • such parameters are each independent of one another.
  • each internucleoside linkage of an antisense and/or sense strand having a particular sugar motif may be modified or unmodified and may or may not follow the modification pattern of the sugar modifications.
  • the internucleoside linkages within the antisense strand may be the same or different from one another and may be the same or different from the internucleoside linkages of the sense strand, even if the antisense and sense strands have the same motif of sugar modifications.
  • all modifications are independent of nucleobase sequence.
  • Preferred modification patterns for the antisense and/or sense strands of double-stranded oligonucleotides of the invention are set out below.
  • modification patterns are independent of the nucleobase sequence of a given antisense and/or sense strand of a double-stranded oligonucleotide.
  • any modification pattern of an antisense strand as described herein may be combined equally and without reservation with any antisense nucleobase sequence described herein.
  • any modification pattern of a sense strand as described herein may be combined equally and without reservation with any antisense nucleobase sequence described herein.
  • a double stranded oligonucleotide of the invention may comprise an antisense strand having any one of the modification patterns, as shown in Figure 1.
  • a double stranded oligonucleotide of the invention may comprise an antisense strand having any one of the following modification patterns: (a) 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][mRN][mRN][fRN][mRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][f RN][mRN][f RN][mRN][f RN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN
  • Each [modN] may be independently selected from any XNA as described herein, a 2’-O-methyl modified nucleotide or a 2’-fluoro modified nucleotide.
  • each [modN] may be independently selected from a GNA, a DNA, a UNA, a 2’-O-methyl modified nucleotide or a 2’-fluoro modified nucleotide.
  • the [modR] at position 7 is modified with an XNA, more preferably wherein the [modR] at position 7 is a GNA, DNA, UNA, SNA or 2’F-ANA.
  • the two 5’ most internucleoside linkages in the above antisense strand are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise a sense strand having any one of the modification patterns, as shown in Figure 2.
  • a double stranded oligonucleotide of the invention may comprise a sense strand having any one of the following modification patterns: (a) 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mR N][fRN][mRN][fRN][mRN]3’; (b) 5’[fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][m
  • the two 5’ most internucleoside linkages in the above sense strand are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][fRN][mRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN]3’; and a sense strand having the modification pattern: 5’[fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mR N][fRN][mRN][fRN][mRN][fRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleot
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][fR N][mRN][fRN][mRN]3’; and a sense strand having the modification pattern: 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mR N][mRN][mRN][mRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleotide and [fRN] stands for a 2’-fluoro modified nucleo
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’[mRN][fRN][mRN][fRN][mRN][fRN][mRN][fRN][mRN][mRN][mRN][mRN][fRN][mRN][mRN][fRN][mRN][mRN][mRN][mRN]3’; and a sense strand having the modification pattern: 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’[mRN][fRN][mRN][mRN][mRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; and a sense strand having the modification pattern: 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mR N][mRN][mRN][mRN][mRN][mRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleotide and [f
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • a double stranded oligonucleotide of the invention may comprise an antisense sense strand having the modification pattern: 5’[mRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mR N][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; and a sense strand having the modification pattern: 5’[mRN][mRN][mRN][mRN][mRN][mRN][mRN][fRN][fRN][fRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN][mRN]3’; wherein [mRN] stands for a 2’-O-methyl modified nucleot
  • the two 5’ most internucleoside linkages are phosphorothioate internucleoside linkages and the two 3’ most internucleoside linkages are phosphorothioate internucleoside linkages.
  • Polynucleotide Conjugates The invention also provides a polynucleotide conjugate comprising a double-stranded oligonucleotide of the invention and a conjugate group. Thus, a double-stranded oligonucleotide of the invention may be covalently attached to one or more conjugate groups.
  • a conjugate group may be attached to the antisense strand and/or the sense strand of a double- stranded oligonucleotide of the invention.
  • a conjugate group may be attached to the 5’ and/or 3’ end of the sense strand, the antisense strand or both the sense strand and antisense strand.
  • Different conjugate groups may be attached to the sense and/or antisense strand, and/or to the 5’ and/or 3’ end of said strands. Where different conjugate groups are used, they may be selected independently.
  • a conjugate group may preferably be attached to the sense strand of a double-stranded oligonucleotide of the invention, particularly to the 3’ end of the sense strand.
  • references herein to attachment of a conjugate group to a double-stranded oligonucleotide of the invention refers to both attachment of said conjugate group to the sense strand and/or antisense strand at the 5’ and/or 3’ end unless expressly stated to the contrary.
  • a conjugate group may modify one or more properties of the attached double-stranded oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. Conjugation of one or more carbohydrate moieties to a double-stranded oligonucleotide of the invention can optimize one or more properties of the modified oligonucleotide.
  • the carbohydrate moiety may be attached to a modified subunit of the modified oligonucleotide.
  • the ribose sugar of one or more ribonucleotide subunits of a modified oligonucleotide can be replaced with another moiety, e.g. a non-carbohydrate (preferably cyclic) carrier to which is attached a carbohydrate ligand.
  • a ribonucleotide subunit in which the ribose sugar of the subunit has been so replaced is referred to herein as a ribose replacement modification subunit (RRMS), which is a modified sugar moiety.
  • RRMS ribose replacement modification subunit
  • a cyclic carrier may be a carbocyclic ring system, i.e., one or more ring atoms may be a heteroatom, e.g., nitrogen, oxygen, sulphur.
  • the cyclic carrier may be a monocyclic ring system, or may contain two or more rings, e.g. fused rings.
  • the cyclic carrier may be a fully saturated ring system, or it may contain one or more double bonds.
  • conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide.
  • conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053- 1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem.
  • Acids Res., 1990, 18, 3777-3783 a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp.
  • polynucleotide conjugates which comprise or consist of a double-stranded oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups.
  • Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide.
  • Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2'- position of a nucleoside of the antisense and/or sense strand of a double-stranded oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of the antisense and/or sense strand of a double-stranded oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3’ and/or 5’-end of the antisense and/or sense strand of a double-stranded oligonucleotide.
  • conjugate groups are attached at the 3’-end of the antisense and/or sense strand of a double-stranded oligonucleotide. In certain embodiments, conjugate groups are attached near the 3’-end of the antisense and/or sense strand of a double-stranded oligonucleotide. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5’-end of the antisense and/or sense strand of a double-stranded oligonucleotide. In certain embodiments, conjugate groups are attached near the 5’-end of the antisense and/or sense strand of a double-stranded oligonucleotide.
  • terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.
  • a conjugate group may comprise or consist of a conjugate linker and/or a conjugate moiety, such as those described herein.
  • Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates (e.g., GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.
  • intercalators include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates (e.g., GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, phospholipids, bio
  • a conjugate moiety may comprise an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.
  • an active drug substance for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, car
  • Conjugate Linkers are typically attached to the sense and/or antisense strands through conjugate linkers.
  • the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond).
  • the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.
  • a conjugate linker comprises pyrrolidine.
  • a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.
  • conjugate linkers are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to compounds, such as the oligonucleotides provided herein.
  • a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to bind to a particular site on a compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups.
  • bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.
  • conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA).
  • conjugate linkers include but are not limited to substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl or substituted or unsubstituted C 2 -C 10 alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.
  • conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides.
  • conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine.
  • a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6- N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the sense and/or antisense strand of a double-stranded oligonucleotide after it reaches a target tissue.
  • linker-nucleosides are typically linked to one another and to the remainder of the sense and/or antisense strand of a double-stranded oligonucleotide through cleavable bonds.
  • cleavable bonds are phosphodiester bonds.
  • linker-nucleosides are not considered to be part of the sense and/or antisense strand of a double- stranded oligonucleotide.
  • a sense and/or antisense strand of a double- stranded oligonucleotide consists of a specified number or range of linked nucleosides and the sense and/or antisense strand of the double-stranded oligonucleotide also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the sense and/or antisense strand and are not used in determining the percent identity/complementarity of the sense and/or antisense strand for the reference nucleic acid.
  • polynucleotide conjugate may comprise (1) an antisense strand of a double-stranded oligonucleotide consisting of 19-23 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the antisense strand.
  • the total number of contiguous linked nucleosides in such an antisense strand within a polynucleotide conjugate may be more than 23.
  • polynucleotide conjugate may comprise an antisense strand of a double-stranded oligonucleotide consisting of 19-23 nucleosides and no conjugate group.
  • conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker- nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside. In certain embodiments, conjugate linkers comprise 1-3 linker- nucleosides.
  • a conjugate group it is desirable for a conjugate group to be cleaved from the sense and/or antisense strand of a double-stranded oligonucleotide.
  • polynucleotide conjugates comprising a particular conjugate moiety are better taken up by a particular cell type, but once the polynucleotide conjugate has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent double-stranded oligonucleotide.
  • certain conjugate linkers may comprise one or more cleavable moieties.
  • a cleavable moiety is a cleavable bond.
  • a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.
  • a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide (e.g. an antisense or sense strand) and a conjugate moiety or conjugate group.
  • an oligonucleotide e.g. an antisense or sense strand
  • a cleavable moiety comprises or consists of one or more linker-nucleosides.
  • the one or more linker-nucleosides are linked to one another and/or to the remainder of the polynucleotide conjugate through cleavable bonds.
  • such cleavable bonds are unmodified phosphodiester bonds.
  • a cleavable moiety is 2'-deoxynucleoside that is attached to either the 3' or 5'-terminal nucleoside of the sense and/or antisense strand by a phosphate internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage.
  • the cleavable moiety is 2'-deoxyadenosine.
  • the conjugate group is attached to the antisense strand at the 5’-end of antisense strand.
  • the conjugate group is attached to the antisense strand at the 3’-end of the antisense strand.
  • the conjugate group is attached to the sense strand at the 5’-end of sense strand. In certain embodiments, the conjugate group is attached to the sense strand at the 3’-end of the sense strand. Typically, the conjugate group is attached to the 5’-end or the 3’-end of the sense strand. Preferably, the conjugate group is attached to the sense strand at the 3’-end of the sense strand. In certain embodiments, the conjugate group comprises N-acetyl galactosamine. In certain embodiments, the conjugate group comprises a cell-targeting moiety having an affinity for transferrin receptor (TfR), also known as TfR1 and CD71.
  • TfR transferrin receptor
  • the conjugate group comprises an anti-TfR1 antibody or fragment thereof. In certain embodiments, the conjugate group comprises a protein or peptide capable of binding TfR1. In certain embodiments, the conjugate group comprises an aptamer capable of binding TfR1.
  • conjugate groups may be selected from any of a C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C22 alkenyl, C20 alkenyl, C16 alkenyl, C10 alkenyl, C21 alkenyl, C19 alkenyl, C18 alkenyl, C15 alkenyl, C14 alkenyl, C13 alkenyl, C12 alkenyl, C11 alkenyl, C9 alkenyl, C8 alkenyl, C7 alkenyl, C6 alkenyl, or C5 alkenyl.
  • conjugate groups may be selected from any of C22 alkyl, C20 alkyl, C16 alkyl, C10 alkyl, C21 alkyl, C19 alkyl, C18 alkyl, C15 alkyl, C14 alkyl, C13 alkyl, C12 alkyl, C11 alkyl, C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, and C5 alkyl, where the alkyl chain has one or more unsaturated bonds.
  • an antisense agent comprises a double-stranded oligonucleotide as described herein, or a polynucleotide conjugate comprising said double-stranded oligonucleotide and a conjugate group.
  • Said antisense agent is typically an RNAi agent capable of reducing the amount of PSD3 nucleic acid through the activation of RISC/Ago2.
  • Certain embodiments provide an oligomeric agent comprising two or more double-stranded oligonucleotides.
  • an oligomeric agent comprises two or more of any of the double- stranded oligonucleotides described herein.
  • an oligomeric agent comprises two or more of the same double-stranded oligonucleotides, which can be any of the double-stranded oligonucleotides described herein.
  • the two or more double-stranded oligonucleotides are linked together.
  • the two or more double-stranded oligonucleotides are covalently linked together.
  • the sense strands of the two or more double-stranded oligonucleotides are covalently linked together.
  • the sense strands of two or more double-stranded oligonucleotides are covalently linked together at their 3’ ends.
  • the two or more double-stranded oligonucleotides are covalently linked together by a glycol linker, such as a tetraethylene glycol linker.
  • a glycol linker such as a tetraethylene glycol linker.
  • Certain such compounds are described in, e.g., Alterman, et al., Nature Biotech., 37:844-894, 2019.
  • Cell-Targeting Moieties may comprise a cell-targeting moiety.
  • a conjugate group may have the general formula: wherein n is from 1 to about 3, m is 0 when n is 1, m is 1 when n is 2 or greater, j is 1 or 0, and k is 1 or 0. In certain embodiments, n is 1, j is 1 and k is 0.
  • cell-targeting moieties comprise two tethered ligands covalently attached to a branching group.
  • Each ligand of a cell-targeting moiety may have an affinity for at least one type of receptor on a target cell.
  • each ligand has an affinity for at least one type of receptor on the surface of a mammalian liver cell.
  • each ligand has an affinity for the hepatic asialoglycoprotein receptor (ASGP-R).
  • each ligand is a carbohydrate.
  • a conjugate group may comprise a cell-targeting conjugate moiety.
  • Said conjugate group may have the general formula: wherein n is from 1 to about 3, m is 0 when n is 1, m is 1 when n is 2 or greater, j is 1 or 0, and k is 1 or 0. In certain embodiments, n is 1, j is 1 and k is 0. In certain embodiments, n is 1, j is 0 and k is 1. In certain embodiments, n is 1, j is 1 and k is 1. In certain embodiments, n is 2, j is 1 and k is 0. In certain embodiments, n is 2, j is 0 and k is 1. In certain embodiments, n is 2, j is 1 and k is 1. In certain embodiments, n is 3, j is 1 and k is 0.
  • Conjugate groups may comprise cell-targeting moieties that have at least one tethered ligand.
  • Cell- targeting moieties may comprise two tethered ligands covalently attached to a branching group.
  • cell-targeting moieties comprise three tethered ligands covalently attached to a branching group.
  • each ligand of a cell-targeting moiety has an affinity for at least one type of receptor on a target cell.
  • each ligand has an affinity for at least one type of receptor on the surface of a mammalian liver cell. In certain embodiments, each ligand has an affinity for the hepatic asialoglycoprotein receptor (ASGP-R). In certain embodiments, each ligand is a carbohydrate. In certain embodiments, each ligand is, independently selected from galactose, N-acetyl galactoseamine (GalNAc), mannose, glucose, glucoseamine and fucose. In certain preferred embodiments, each ligand is N-acetyl galactoseamine (GalNAc). In certain embodiments, the cell-targeting moiety comprises 3 GalNAc ligands.
  • the cell-targeting moiety comprises 2 GalNAc ligands. In certain embodiments, the cell- targeting moiety comprises 1 GalNAc ligand.
  • Each ligand of a cell-targeting moiety may be a carbohydrate, carbohydrate derivative, modified carbohydrate, polysaccharide, modified polysaccharide, or polysaccharide derivative.
  • the conjugate group comprises a carbohydrate cluster (see, e.g., Maier et al., “Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Cluster for Cellular Targeting,” Bioconjugate Chemistry, 2003, 14, 18-29 or Rensen et al., “Design and Synthesis of Novel N-Acetylgalactos- amine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein Receptor,” J. Med. Chem. 2004, 47, 5798-5808).
  • each ligand is an amino sugar or a thio sugar.
  • amino sugars may be selected from any number of compounds known in the art, such as sialic acid, ⁇ - D-galactosamine, ⁇ -muramic acid, 2-deoxy-2-methylamino-L-glucopyranose, 4,6-dideoxy-4-formamido-2,3-di- O-methyl-D-mannopyranose, 2-deoxy-2-sulfoamino-D-glucopyranose and N-sulfo-D-glucosamine, and N- glycoloyl- ⁇ -neuraminic acid.
  • thio sugars may be selected from 5-Thio- ⁇ -D-glucopyranose, methyl 2,3,4-tri-O-acetyl-1-thio-6-O-trityl- ⁇ -D-glucopyranoside, 4-thio- ⁇ -D-galactopyranose, and ethyl 3,4,6,7-tetra-O- acetyl-2-deoxy-1,5-dithio- ⁇ -D-gluco-heptopyranoside.
  • compounds comprise a conjugate group having the formula:
  • Representative United States patents, United States patent application publications, international patent application publications, and other publications that teach the preparation of certain of the above noted conjugate groups, compounds comprising conjugate groups, tethers, conjugate linkers, branching groups, ligands, cleavable moieties as well as other modifications include without limitation, US 5,994,517, US 6,300,319, US 6,660,720, US 6,906,182, US 7,262,177, US 7,491,805, US 8,106,022, US 7,723,509, US 2006/0148740, US 2011/0123520, WO 2013/033230 and WO 2012/037254, Biessen et al., J. Med. Chem.
  • a preferred conjugate group is a GalNAc.
  • Said GalNAc may be present at the 5’ and/or the 3’ of (i) the antisense strand and/or (ii) the sense strand.
  • GalNAc is present at the 5’ and/or 3’ end of the sense strand, more preferably at the 3’ end of the sense strand.
  • a particularly preferred GalNAc conjugate group of the invention has the following structure: Populations of Double-Stranded Oligonucleotides Populations of double-stranded oligonucleotides in which a majority (e.g. at least 70%, at least 80%, at least 90%, at least 95% or more) or all of the double-stranded oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations.
  • All of the chiral centers of all of the double-stranded oligonucleotides are stereorandom in a stereorandom population.
  • at least one particular chiral center is not stereorandom in the double-stranded oligonucleotides of the population (e.g. in the antisense and/or sense strand).
  • the double-stranded oligonucleotides of a chirally enriched population are enriched for ⁇ -D ribosyl sugar moieties, and all of the phosphorothioate internucleoside linkages (of the antisense and/or sense strand) are stereorandom.
  • the double-stranded oligonucleotides of a chirally enriched population are enriched for both ⁇ -D ribosyl sugar moieties and at least one, particular phosphorothioate internucleoside linkage in a particular stereochemical configuration.
  • the invention therefore provides a chirally enriched population of double-stranded oligonucleotide as herein, or the polynucleotide conjugates comprising said double-stranded oligonucleotide, wherein the population is enriched for double-stranded oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage (in the antisense and/or sense strand) having a particular stereochemical configuration.
  • Said chirally enriched population may be enriched for double-stranded oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage (in the antisense and/or sense strand) having the (Sp) or (Rp) configuration, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • Said chirally enriched population may be enriched for double-stranded oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage (in the antisense and/or sense strand), or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • Said chirally enriched population may be enriched for double-stranded oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage (in the antisense and/or sense strand) and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages (in the antisense and/or sense strand), or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • Said chirally enriched population may be enriched for double-stranded oligonucleotides having at least 2 or 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5’ to 3’ direction, or polynucleotide conjugates comprising said double-stranded oligonucleotides.
  • a linker from the sense strand to a GalNAc may contain 0, 1, 2 or 3 phosphorothioate internucleoside linkages.
  • the invention also provides a population of double-stranded oligonucleotides comprising double-stranded oligonucleotides as described herein, or the polynucleotide conjugates comprising said double-stranded oligonucleotides, wherein all of the phosphorothioate internucleoside linkages of the double-stranded oligonucleotides are stereorandom.
  • Double-stranded oligonucleotides of the invention are typically capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity; such double-stranded oligonucleotides, and particularly the antisense strands thereof, are antisense compounds.
  • An antisense compound i.e. a double-stranded oligonucleotide of the invention, has antisense activity when it reduces or inhibits the amount or activity of a target nucleic acid by 25% or more in the standard cell assay.
  • An antisense compound i.e.
  • a double-stranded oligonucleotide of the invention may reduce or inhibit the amount or activity of a target nucleic acid by 30% or more, 35% or more, 40% or more, 45% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, or 95% or more in the standard cell assay, up to complete inhibition of the amount or activity of the target nucleic acid.
  • a double-stranded oligonucleotide of the invention may reduce or inhibit the amount or activity of a target nucleic acid by 75% or more in the standard cell assay.
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 30; 31; 34; 35; 54; 55; 74; 75; 114; 115; 118; 119; 122; 123; 134; 135; 142; 143; 158; 159; 194; 195; 250; 251; 262; 263; 278; 279; 282; 283; 286; 287; 290; 291; 366; 367; 374; 375; 382; 383; 386; 387; 390; 391; 398; 399; 414; 415; 418; 419; 426; 427; 466; 467; 470; 471; 478; 479
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 30; 34; 54; 74; 114; 118; 122; 134; 142; 158; 194; 250; 262; 278; 282; 286; 290; 366; 374; 382; 386; 390; 398; 414; 418; 426; 466; 470; 478; 494; 498; 502; 506; 510; 522; 538; 542; 566; 570; 574; 586; 606; 610; 618; 622; 626; 630; 634; 654; 666; 678; 694; 698; 702; 706; 718; 722; 726; 730; 738; 742; 750; 758; 762; 770; 774; 778; 794; 798; 802; 822; 830; 838; 842;
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 31; 35; 55; 75; 115; 119; 123; 135; 143; 159; 195; 251; 263; 279; 283; 287; 291; 367; 375; 383; 387; 391; 399; 415; 419; 427; 467; 471; 479; 495; 499; 503; 507; 511; 523; 539; 543; 567; 571; 575; 587; 607; 611; 619; 623; 627; 631; 635; 655; 667; 679; 695; 699; 703; 707; 719; 723; 727; 731; 739; 743; 751; 759; 763; 771; 775; 779; 795; 799; 803; 823; 831; 839; 843;
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 34; 35; 54; 55; 142; 143; 158; 159; 250; 251; 262; 263; 282; 283; 286; 287; 390; 391; 398; 399; 426; 427; 470; 471; 478; 479; 494; 495; 502; 503; 522; 523; 566; 567; 574; 575; 586; 587; 606; 607; 618; 619; 626; 627; 654; 655; 666; 667; 678; 679; 694; 695; 698; 699; 722; 723; 730; 731; 742; 743; 778; 779; 802; 803; 822; 823; 830; 831; 842; 843; 846; 847; 858; 859; 8
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 34; 54; 142; 158; 250; 262; 282; 286; 390; 398; 426; 470; 478; 494; 502; 522; 566; 574; 586; 606; 618; 626; 654; 666; 678; 694; 698; 722; 730; 742; 778; 802; 822; 830; 842; 846; 858; 862; 866; 870; 874; 878; 886; 906; 914; 954; 970; 978; 1022; 1026; 1034; 1038; 1042; 1058; 1082; 1086; 1102; 1118; 1126; 1142; 1146; 1150; 1154; 1158; 1182; 1186; 1190; 1214; 1254; 1270; 1274; 1278; 1294; 1298
  • the nucleobase sequence of the antisense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 35; 55; 143; 159; 251; 263; 283; 287; 391; 399; 427; 471; 479; 495; 503; 523; 567; 575; 587; 607; 619; 627; 655; 667; 679; 695; 699; 723; 731; 743; 779; 803; 823; 831; 843; 847; 859; 863; 867; 871; 875; 879; 887; 907; 915; 955; 971; 979; 1023; 1027; 1035; 1039; 1043; 1059; 1083; 1087; 1103; 1119; 1127; 1143; 1147; 1151; 1155; 1159; 1183; 1187; 1191; 1215; 1255; 1271; 1275; 1279; 1295; 12
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 32; 33; 36; 37; 56; 57; 76; 77; 116; 117; 120; 121; 124; 125; 136; 137; 144; 145; 160; 161; 196; 197; 252; 253; 264; 265; 280; 281; 284; 285; 288; 289; 292; 293; 368; 369; 376; 377; 384; 385; 388; 389; 392; 393; 400; 401; 416; 417; 420; 421; 428; 429; 468; 469; 472; 473; 480; 481; 496; 497; 500; 501; 504; 505; 508; 509; 512; 513; 524; 525; 540; 541; 544; 545; 568; 569; 5
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 32; 36; 56; 76; 116; 120; 124; 136; 144; 160; 196; 252; 264; 280; 284; 288; 292; 368; 376; 384; 388; 392; 400; 416; 420; 428; 468; 472; 480; 496; 500; 504; 508; 512; 524; 540; 544; 568; 572; 576; 588; 608; 612; 620; 624; 628; 632; 636; 656; 668; 680; 696; 700; 704; 708; 720; 724; 728; 732; 740; 744; 752; 760; 764; 772; 776; 780; 796; 800; 804; 824; 832; 840; 844; 848; 860; 8
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 33; 37; 57; 77; 117; 121; 125; 137; 145; 161; 197; 253; 265; 281; 285; 289; 293; 369; 377; 385; 389; 393; 401; 417; 421; 429; 469; 473; 481; 497; 501; 505; 509; 513; 525; 541; 545; 569; 573; 577; 589; 609; 613; 621; 625; 629; 633; 637; 657; 669; 681; 697; 701; 705; 709; 721; 725; 729; 733; 741; 745; 753; 761; 765; 773; 777; 781; 797; 801; 805; 825; 833; 841; 845;
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 36; 37; 56; 57; 144; 145; 160; 161; 252; 253; 264; 265; 284; 285; 288; 289; 392; 393; 400; 401; 428; 429; 472; 473; 480; 481; 496; 497; 504; 505; 524; 525; 568; 569; 576; 577; 588; 589; 608; 609; 620; 621; 628; 629; 656; 657; 668; 669; 680; 681; 696; 697; 700; 701; 724; 725; 732; 733; 744; 745; 780; 781; 804; 805; 824; 825; 832; 833; 844; 845; 848; 849; 860; 861; 864; 8
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 36; 56; 144; 160; 252; 264; 284; 288; 392; 400; 428; 472; 480; 496; 504; 524; 568; 576; 588; 608; 620; 628; 656; 668; 680; 696; 700; 724; 732; 744; 780; 804; 824; 832; 844; 848; 860; 864; 868; 872; 876; 880; 888; 908; 916; 956; 972; 980; 1024; 1028; 1036; 1040; 1044; 1060; 1084; 1088; 1104; 1120; 1128; 1144; 1148; 1152; 1156; 1160; 1184; 1188; 1192; 1216; 1256; 1272; 1276; 1280; 1296; 1300; 1304;
  • the nucleobase sequence of the sense strand may comprise or consist of a nucleobase sequence that identical to any of SEQ ID NOs: 37; 57; 145; 161; 253; 265; 285; 289; 393; 401; 429; 473; 481; 497; 505; 525; 569; 577; 589; 609; 621; 629; 657; 669; 681; 697; 701; 725; 733; 745; 781; 805; 825; 833; 845; 849; 861; 865; 869; 873; 877; 881; 889; 909; 917; 957; 973; 981; 1025; 1029; 1037; 1041; 1045; 1061; 1085; 1089; 1105; 1121; 1129; 1145; 1149; 1153; 1157; 1161; 1185; 1189; 1193; 1217; 1257; 1273; 1277; 1281; 1297; 1301
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 30+32; 34+36; 54+56; 74+76; 114+116; 118+120; 122+124; 134+136; 142+144; 158+160; 194+196; 250+252; 262+264; 278+280; 282+284; 286+288; 290+292; 366+368; 374+376; 382+384; 386+388; 390+392; 398+400; 414+416; 418+420; 426+428; 466+468; 470+472; 478+480; 494
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 31+33; 35+37; 55+57; 75+77; 115+117; 119+121; 123+125; 135+137; 143+145; 159+161; 195+197; 251+253; 263+265; 279+281; 283+285; 287+289; 291+293; 367+369; 375+377; 383+385; 387+389; 391+393; 399+401; 415+417; 419+421; 427+429; 467+469; 471+473; 479+48
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 34+36; 54+56; 142+144; 158+160; 250+252; 262+264; 282+284; 286+288; 390+392; 398+400; 426+428; 470+472; 478+480; 494+496; 502+504; 522+524; 566+568; 574+576; 586+588; 606+608; 618+620; 626+628; 654+656; 666+668; 678+680; 694+696; 698+700; 722+724;
  • a double-stranded oligonucleotide of the invention may have an antisense strand and a sense strand of any pair of SEQ ID NOs: A+B as set out below, wherein SEQ ID NO: A is the nucleobase sequence of the antisense strand, and SEQ ID NO: B is the nucleobase sequence of the sense strand: SEQ ID NOs: 35+37; 55+57; 143+145; 159+161; 251+253; 263+265; 283+285; 287+289; 391+393; 399+401; 427+429; 471+473; 479+481; 495+497; 503+505; 523+525; 567+569; 575+577; 587+589; 607+609; 619+621; 627+629; 655+657; 667+669; 679+681; 695+697; 699+701; 7
  • Antisense compounds i.e. double-stranded oligonucleotides of the invention, may selectively affect one or more target nucleic acid.
  • Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity.
  • Hybridization of an antisense compound to a target nucleic acid may result in recruitment of a protein that cleaves the target nucleic acid.
  • certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid.
  • RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex.
  • the DNA in such an RNA:DNA duplex need not be unmodified DNA.
  • antisense compounds that are sufficiently “DNA-like” to elicit RNase H activity. Hybridization of an antisense compound to a target nucleic acid may not result in recruitment of a protein that cleaves that target nucleic acid. Instead, hybridization of an antisense compound to the target nucleic acid may result in alteration of splicing of the target nucleic acid.
  • hybridization of an antisense compound to a target nucleic acid may result in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid, and/or may result in alteration of translation of the target nucleic acid.
  • an antisense compound or a portion of an antisense compound e.g. the antisense strand of a double-stranded oligonucleotide of the invention
  • RISC RNA-induced silencing complex
  • certain antisense compounds result in cleavage of the target nucleic acid by Argonaute.
  • RNAi compounds that are loaded into RISC are RNAi compounds.
  • RNAi compounds may be double- stranded (siRNA or dsRNAi) or single-stranded (ssRNA).
  • the double-stranded oligonucleotides of the invention are preferably siRNA.
  • Antisense activities may be observed directly or indirectly.
  • observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein and/or a phenotypic change in a cell or animal.
  • the antisense strand of a double-stranded oligonucleotide of the invention typically comprises or consists of an oligonucleotide comprising a region that is (reverse) complementary to a target nucleic acid.
  • the target nucleic acid is a PSD3 transcript as described herein, particularly that of SEQ ID NO: 1.
  • the target nucleic acid may be an endogenous RNA molecule.
  • the target nucleic acid may encode a protein.
  • the target nucleic acid may be selected from: a mature mRNA and a pre-mRNA, including intronic, exonic and untranslated regions.
  • the target RNA may be a mature mRNA.
  • the target nucleic acid may be a pre-mRNA.
  • the target region may be entirely within an intron.
  • the target region may span an intron/exon junction.
  • the target region may be at least 50% within an intron.
  • the target nucleic acid is a PSD3 transcript as described herein, particularly that of SEQ ID NO: 1.
  • An antisense strand of a double-stranded oligonucleotide of the invention may be complementary to the target nucleic acid over the entire length of the antisense strand.
  • the antisense strand may be 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid.
  • antisense strands may be at least 80% complementary to the target nucleic acid over the entire length of the antisense strand and comprise a region that is 100% or fully complementary to a target nucleic acid.
  • the region of full complementarity is typically from 6 to 23, 6 to 21, 6 to 20, 10 to 23, 10 to 21, 10 to 19, 19 to 23, 19 to 21, or 18 to 20 nucleobases in length.
  • the region of full complementarity may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleobases in length, up to the full length of the antisense strand.
  • An antisense strand of the invention may comprise no more than 5, no more than 4, no more than 3, no more than 2, no more than 1, or no mismatches.
  • a sense strand of a double-stranded oligonucleotide of the invention may be identical to the target nucleic acid over the entire length of the sense strand.
  • the sense strand may be 99%, 95%, 90%, 85%, or 80% identical to the target nucleic acid.
  • sense strands may be at least 80% identical to the target nucleic acid over the entire length of the sense strand and comprise a region that is 100% or fully identical to a target nucleic acid.
  • the region of full identity is typically from 6 to 23, 6 to 21, 6 to 20, 10 to 23, 10 to 21, 10 to 19, 19 to 23, 19 to 21, or 18 to 20 nucleobases in length.
  • the region of full identity may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 nucleobases in length, up to the full length of the sense strand.
  • a sense strand of the invention may comprise no more than 5, no more than 4, no more than 3, no more than 2, no more than 1, or no mismatches. It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al (J. Natl.
  • the antisense strand and/or sense strand of a double-stranded oligonucleotide of the invention may comprise one or more mismatched nucleobases relative to the target nucleic acid.
  • antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount.
  • selectivity of the oligonucleotide is improved.
  • the mismatch may be specifically positioned. In certain of the antisense and/or sense strands, preferably both the antisense and sense strand do not contain any mismatches.
  • double-stranded oligonucleotides of the invention comprise or consist of an antisense strand comprising a region that is complementary to a target nucleic acid and a sense strand comprising a region that is identical to the target nucleic acid, wherein the target nucleic acid is expressed in a pharmacologically relevant tissue.
  • the pharmacologically relevant tissues are the liver cells and tissues.
  • the invention also provides methods of inhibiting PSD3 expression, which can be useful for treating a disease associated with PSD3 in a subject, by administration of a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid.
  • the PSD3 target nucleic acid may be as described herein.
  • the double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, population of double-stranded oligonucleotides and pharmaceutical composition may be as described herein.
  • diseases associated with PSD3 treatable with a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, and methods provided herein include liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • a method of the invention may comprise administering to a subject a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid.
  • the subject may have liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis chronic hepatitis
  • hereditary hemochromatosis hereditary hemochromatosis
  • primary sclerosing cholangitis may have liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic stea
  • a method of treating liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis in a subject may comprise administering to the subject a therapeutically effective amount of a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, thereby treating the subject.
  • FLD fatty
  • Administering the therapeutically effective amount of the double-stranded oligonucleotide, the polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these may reduce liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation in the subject.
  • the invention also provides a method of inhibiting expression of PSD3 nucleic acid, such as RNA, in a subject having a disease associated with PSD3 comprises administering to the subject a double- stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, thereby inhibiting expression of PSD3 nucleic acid in the subject.
  • a method of inhibiting expression of PSD3 nucleic acid such as RNA
  • Administering the double-stranded oligonucleotide, polynucleotide conjugate comprising a double- stranded oligonucleotide, population of double-stranded oligonucleotides, or pharmaceutical composition comprising any of these may inhibit expression of PSD3 in the liver.
  • the subject may have liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis chronic hepatitis
  • hereditary hemochromatosis hereditary hemochromatosis
  • primary sclerosing cholangitis may have liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic stea
  • Also provided is a method of inhibiting expression of PSD3 nucleic acid in a cell comprising contacting the cell with an a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, thereby inhibiting expression of PSD3 nucleic acid in the cell.
  • the cell may preferably be a liver cell.
  • the cell may be in a subject having liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis chronic hepatitis
  • hereditary hemochromatosis hereditary hemochromatosis
  • primary sclerosing cholangitis primary sclerosing cholangitis.
  • the invention also provides a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, for use in treating a disease associated with PSD3.
  • the disease may be liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis hereditary hemochromatosis
  • primary sclerosing cholangitis may be primary sclerosing cholangitis.
  • the double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, population of double-stranded oligonucleotides, or pharmaceutical composition comprising any of these may be for use in reducing liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation associated with liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non- alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • the invention also provides the use of a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid for the manufacture or preparation of a medicament for treating a disease associated with PSD3.
  • the disease may be liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD fatty liver disease
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis
  • chronic hepatitis hereditary hemochromatosis
  • primary sclerosing cholangitis may be primary sclerosing cholangitis.
  • the double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, population of double-stranded oligonucleotides, or pharmaceutical composition comprising any of these may be for the manufacture or preparation of a medicament for reducing liver damage, steatosis, liver fibrosis, liver inflammation, liver scarring or cirrhosis, liver failure, liver enlargement, elevated transaminases, or hepatic fat accumulation associated with liver disease, fatty liver disease (FLD), nonalcoholic fatty liver disease (NAFLD), hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver cirrhosis, hepatocellular carcinoma, alcoholic liver disease, alcoholic steatohepatitis (ASH), HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primary sclerosing cholangitis.
  • FLD
  • the double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these may preferably be any described herein.
  • Pharmaceutical Compositions The invention provides pharmaceutical compositions comprising one or more double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, a population of double-stranded oligonucleotides, or a pharmaceutical composition comprising any of these, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable diluent or carrier.
  • the pharmaceutically acceptable diluent may be water or saline.
  • a pharmaceutical composition may comprise or consist of a sterile saline solution and one or more double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid.
  • the sterile saline is preferably pharmaceutical grade saline.
  • a pharmaceutical composition may comprise or consist of one or more double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, or a population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid and sterile water.
  • the sterile water is pharmaceutical grade water, e.g., water for injection.
  • the saline may be phosphate-buffered saline (PBS), preferably sterile PBS.
  • a pharmaceutical composition may comprise one or more double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid and one or more excipients.
  • Excipients may be selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, or a population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
  • Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.
  • compositions comprising a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, or a population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, encompass any pharmaceutically acceptable salts of the double-stranded oligonucleotide, polynucleotide conjugate or population of double-stranded oligonucleotides, esters of the double-stranded oligonucleotide, polynucleotide conjugate or population of double-stranded oligonucleotide, or salts of such esters.
  • compositions comprising one or more double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, upon administration to an animal, including a human, are typically capable of providing (directly or indirectly) the biologically active metabolite or residue thereof.
  • the disclosure is also drawn to pharmaceutically acceptable salts of a double-stranded oligonucleotide, a polynucleotide conjugate comprising a double-stranded oligonucleotide, or a population of double-stranded oligonucleotides, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
  • prodrugs comprise one or more conjugate group attached to an oligonucleotide, wherein the conjugate group is cleaved by endogenous nucleases within the body.
  • Lipid moieties have been used in nucleic acid therapies in a variety of methods.
  • the double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids.
  • DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid.
  • a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.
  • a pharmaceutical composition may comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition may comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents of the present invention to specific tissues or cell types.
  • compositions include liposomes coated with a tissue-specific antibody.
  • a pharmaceutical composition may comprise a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical composition may be prepared for administration by injection (e.g., intravenous, subcutaneous, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • aqueous solution such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers.
  • Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphate linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms.
  • oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium.
  • the term “oligonucleotide” is intended to include all such forms.
  • Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms.
  • a structure depicting the free acid of a compound followed by the term “or a salt thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified.
  • a double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, may be in aqueous solution with sodium.
  • a double-stranded oligonucleotide, polynucleotide conjugate comprising a double- stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid, may be in aqueous solution with potassium.
  • a double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid may be in PBS.
  • a double-stranded oligonucleotide, polynucleotide conjugate comprising a double-stranded oligonucleotide, or population of double-stranded oligonucleotides, any of which comprises an antisense strand having a nucleobase sequence complementary to a PSD3 target nucleic acid may be in water.
  • the pH of the solution may be adjusted with NaOH and/or HCl to achieve a desired pH.
  • Nonlimiting Disclosure and Incorporation by Reference Each of the literature and patent publications listed herein is incorporated by reference in its entirety. While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same.
  • Each of the references, GenBank accession numbers, ENSEMBL identifiers, and the like recited in the present application is incorporated herein by reference in its entirety. Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications.
  • RNA or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary.
  • an oligonucleotide comprising a nucleoside comprising a 2’-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2’-OH in place of one 2’-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA).
  • nucleic acid sequences provided herein are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases.
  • an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified nucleobases, such as “AT m CGAUCG,” wherein m C indicates a cytosine base comprising a methyl group at the 5-position.
  • Certain compounds described herein e.g., modified oligonucleotides have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as ⁇ or ⁇ such as for sugar anomers, or as (D) or (L), such as for amino acids, etc.
  • Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds.
  • Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise.
  • tautomeric forms of the compounds herein are also included unless otherwise indicated.
  • compounds described herein are intended to include corresponding salt forms.
  • the compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element.
  • compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the 1 H hydrogen atoms.
  • Isotopic substitutions encompassed by the compounds herein include but are not limited to: 2 H or 3 H in place of 1 H, 13 C or 14 C in place of 12 C, 15 N in place of 14 N, 17 O or 18 O in place of 16 O, and 33 S, 34 S, 35 S, or 36 S in place of 32 S.
  • non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool.
  • radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.
  • SEQ ID NO: 1 ENSEMBL Accession No. ENST00000327040.13 GGCAGTCCCGGGAGCTCAACAAAGAGCACGCGGCGCTGGCCGCCGGCACTCGCGCCCTGAGGCTGCGGCCCCGGAGCGC CCGGCGGCGGTTTCGGCGCGCGCGGGCTGGCGATGGAAGATGGAAGGAAGGAGCGCAGCGGCAGAGACATTTGTTTG GGTGAACAATGCATCTGCACATTCCCAGAGTGTTGCCAAGGCCAAATATGAATTTTTATTTGGCAGATCTGAAGGGAAA GCTCCAGATACTAGTGATCATGGAGGAAGCACTTTACTCCCACCAAATGTCACAAATGAATTTCCAGAATATGGGACCA TGGAGGAAGGTGGAGAAGGCCTAAGGGCTTCTCTGGAATTTGATGGTGAGGCTCTGCCATGCCACCCACAAGAGCAGCA GGGTGTCCAGCCTCTGGGAGGGCTCTTCTCTGGAATTTGATGGTGAGGCTCTGCCATGCCACCCACAAGA
  • Example 1 Design and generation of siRNA libraries
  • the modified sense and antisense single strands as outlined in Tables 3-4 (corresponding unmodified nucleobase sequences shown in Tables 1 and 2) were synthesised on a MerMade48 instrument (Biosearch Technologies) at 1 ⁇ mol scale using conventional manufacturing methods. Unconjugated strands were prepared on controlled-pore glass (CPG) resin functionalised with a universal linker (CUTAG CPG, Sigma-Aldrich).
  • 3’GalNAc conjugates were synthesised on polystyrene resin pre-loaded with a GalNAc-ligand. Standard phosphoramdite chemistry was used. Dimethoxytrityl (DMT)-protected amidites (2’- fluoro, 2’-O-methyl) were purchased from Wuxi or Sigma-Aldrich/Merck. Ancillary synthesis reagents and solvents were purchased from Sigma-Aldrich/Merck, TCI Chemicals or other commercial suppliers. Phosphoramidites were prepared as 0.1 M solutions in either dry MeCN or 15% DMF in dry MeCN.
  • DMT dimethoxytrityl
  • Couplings were carried out using 0.25 M 5-[3,5-Bis(trifluoromethyl)phenyl]-1H-tetrazole (Activator 42®) in MeCN for 3x6 min or 2x8min. Thiolation was performed using 0.2 M Xanthane hydride in pyridine for 6 min. Oxidation was carried out with 0.02 M iodine in tetrahyrofurane/water/pyridine 90.54/9.05/0.41 (v/v/v) for 1 min.
  • the deprotection was continued at 55°C for ⁇ 16 hours in a cleavage chuck (Bioresearch Technologies). After coming to room temperature, the solutions were concentrated under reduced pressure using a Speedvac.
  • the crude oligonucleotide in 200-300 ⁇ L MilliQ- water was precipitated by adding 3M NaOAc (pH 5.2) to a final concentration of 0.3 M sodium acetate.1 mL of 95% ethanol was added and the plate sealed, shaken and kept at -20°C for at least 2 hours or overnight. The plates were centrifuged at 4°C at 3200 x g for at least 15 min and the supernatant removed. The pellets were briefly dried under reduced pressure (Speedvac).
  • CPG resin was used, crude single strands were resuspended in 800 ⁇ L MilliQ-water, shaken at 800 rpm at least 15 min, the plate centrifuged (3200 x g, 30- 60 min), the solution transferred into a fresh plate and dried down by speedvac or freeze-drying. Dry single strands were dissolved in 1x phosphate-buffered saline (PBS) pH 7.4 (Dibco). Identity of oligonucleotides was confirmed by liquid chromatography-mass spectrometry (LC-MS). The amounts were quantified by UV spectrophotometry at 260nm and the solutions normalised to 1 mM using calculated extinction coefficients.
  • PBS phosphate-buffered saline
  • duplexes equimolar amounts of sense strands and antisense strands were combined using a Tecan Fluent or Tecan Freedom Evo liquid handler. The final concentration was 0.5 mM in 1x PBS in a 96-well plate. The plate was sealed and incubated at 95 °C for 7 min with shaking at 900 rpm in a ThermoMixer (Eppendorf). The plate was let to come to rt with shaking over 30 – 60 min. Duplex formation was confirmed on a subset by gel electrophoresis or non-denaturing LC-MS(UV). The unmodified nucleobase sequences of the guide and passenger strands of the 480 test compounds are set out in Table 1.
  • the unmodified nucleobase sequences of the guide and passenger strands of the test compounds shortlisted for GalNAc conjugation are set out in Table 2.
  • Corresponding modified nucleobase sequences of the guide and passenger strands of the 480 test compounds as synthesized are set out in Table 3.
  • the unmodified nucleobase sequences of the guide and passenger strands of the test compounds as synthesized and shortlisted for GalNAc conjugation are set out in Table 4.
  • the compound number for each test compound is given in each of Tables 1-4, such that the unmodified nucleobase (guide and passenger) sequences for a given test compound and their corresponding modified (guide and passenger) sequences can be identified by the compound number.
  • Table 1 Unmodified nucleobase sequences of exemplified double-stranded oligonucleotides Guide SEQ SEQ N o start end 5'-3' nucleobase sequence ID Passenger 5'-3' nucleobase sequence ID NO NO 1 111 129 UCCUUCCAUCUUCCAUCGC 2 GCGAUGGAAGAUGGAAGGA 4 2 139 157 AAACAAAUGUCUCUGCCGCUGCG 6 CAGCGGCAGAGACAUUUGUUU 8 3 162 180 AUGUGCAGAUGCAUUGUUCACCC 10 GUGAACAAUGCAUCUGCACAU 12 4 174 192 AACACUCUGGGAAUGUGCAGAUG 14 UCUGCACAUUCCCAGAGUGUU 16 5 179 197 UUGGCAACACUCUGGGAAUGUGC 18 ACAUUCCCAGAGUGUUGCCAA 20 6 247 265 UUCCUCCAUGAUCACUAGUAUCU 22 AUACUAGUGAUCAUGGAGGAA 24 7 253 271 AAGUGCU
  • start corresponds to the first base of the sense sequence and to the last base of the antisense sequence.
  • Individual compounds in Table 1 may have identical nucleobase sequences but contain different modified sugar moieties and/or different modified internucleoside linkages.
  • start corresponds to the first base of the sense sequence and to the last base of the antisense sequence.
  • Individual compounds in Table 2 may have identical nucleobase sequences but contain different modified sugar moieties and/or different modified internucleoside linkages.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Microbiology (AREA)
  • Plant Pathology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

L'invention concerne des oligonucléotides double brin, des conjugués polynucléotidiques et des compositions et des populations les comprenant, ainsi que des méthodes et des utilisations de ceux-ci pour réduire la quantité ou l'activité de l'ARN de pleckstrine et de domaine sec7 contenant 3 (PSD3) dans une cellule ou un animal, et dans certains cas, réduire la quantité de protéine PSD3 dans une cellule ou un animal. De tels oligonucléotides double brin, conjugués polynucléotidiques et compositions et populations, méthodes et utilisations sont utiles pour traiter les maladies du foie, la maladie du foie gras (FLD), la maladie du foie gras non alcoolique (NAFLD), la stéatose hépatique, la stéatohépatite non alcoolique (NASH), la cirrhose du foie, le carcinome hépatocellulaire, une maladie hépatique alcoolique, la stéatohépatite alcoolique (ASH), l'hépatite du VHC, l'hépatite chronique, l'hémochromatose héréditaire, ou la cholangite sclérosante primitive.
PCT/IB2024/059334 2023-09-26 2024-09-25 Composés et méthodes pour réduire l'expression de psd3 Pending WO2025068896A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB2314724.2 2023-09-26
GBGB2314724.2A GB202314724D0 (en) 2023-09-26 2023-09-26 compounds and methods for reducing psd3 expression

Publications (1)

Publication Number Publication Date
WO2025068896A1 true WO2025068896A1 (fr) 2025-04-03

Family

ID=88599233

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/059334 Pending WO2025068896A1 (fr) 2023-09-26 2024-09-25 Composés et méthodes pour réduire l'expression de psd3

Country Status (2)

Country Link
GB (1) GB202314724D0 (fr)
WO (1) WO2025068896A1 (fr)

Citations (57)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US4845205A (en) 1985-01-08 1989-07-04 Institut Pasteur 2,N6 -disubstituted and 2,N6 -trisubstituted adenosine-3'-phosphoramidites
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5552540A (en) 1987-06-24 1996-09-03 Howard Florey Institute Of Experimental Physiology And Medicine Nucleoside derivatives
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5614617A (en) 1990-07-27 1997-03-25 Isis Pharmaceuticals, Inc. Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5645985A (en) 1991-11-26 1997-07-08 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5830653A (en) 1991-11-26 1998-11-03 Gilead Sciences, Inc. Methods of using oligomers containing modified pyrimidines
US5859221A (en) 1990-01-11 1999-01-12 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5994517A (en) 1995-11-22 1999-11-30 Paul O. P. Ts'o Ligands to enhance cellular uptake of biomolecules
US6005087A (en) 1995-06-06 1999-12-21 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
WO2004076639A2 (fr) * 2003-02-26 2004-09-10 Wyeth Compositions et methodes destinees a diagnostiquer et traiter des maladies auto-immunes
US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
WO2008101157A1 (fr) 2007-02-15 2008-08-21 Isis Pharmaceuticals, Inc. Nucléosides modifiés 5'-substitués-2'-f et composés oligomères préparés à partir de ceux-ci
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
WO2009111658A2 (fr) * 2008-03-05 2009-09-11 Alnylam Pharmaceuticals, Inc. Compositions et procédés pour inhiber l’expression des gènes eg5 et vegf
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7875733B2 (en) 2003-09-18 2011-01-25 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation
US20110123520A1 (en) 2008-04-11 2011-05-26 Alnylam Pharmaceuticals, Inc. Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
WO2011133876A2 (fr) 2010-04-22 2011-10-27 Alnylam Pharmaceuticals, Inc. Oligonucléotides comprenant des nucléosides acycliques et abasiques, et analogues
US20110313020A1 (en) 2008-12-03 2011-12-22 Marina Biotech, Inc. UsiRNA Complexes
US8088904B2 (en) 2007-08-15 2012-01-03 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8106022B2 (en) 2007-12-04 2012-01-31 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
WO2012037254A1 (fr) 2010-09-15 2012-03-22 Alnylam Pharmaceuticals, Inc. Agents à base d'arni modifiés
US8314227B2 (en) 2007-05-22 2012-11-20 Marina Biotech, Inc. Hydroxymethyl substituted RNA oligonucleotides and RNA complexes
US20130011922A1 (en) 2007-03-02 2013-01-10 F/K/A Mdrna, Inc. Nucleic acid compounds for inhibiting gene expression and uses thereof
WO2013033230A1 (fr) 2011-08-29 2013-03-07 Isis Pharmaceuticals, Inc. Complexes oligomère-conjugué et leur utilisation
US20130203836A1 (en) 2010-04-01 2013-08-08 Isis Pharmaceuticals, Inc. 2' and 5' modified monomers and oligonucleotides
WO2014179620A1 (fr) 2013-05-01 2014-11-06 Isis Pharmaceuticals, Inc. Composés antisens conjugués et leur utilisation
WO2015106128A2 (fr) 2014-01-09 2015-07-16 Alnylam Pharmaceuticals, Inc. Agents d'arni modifiés
WO2017015555A1 (fr) 2015-07-22 2017-01-26 Wave Life Sciences Ltd. Compositions d'oligonucléotides et procédés associés
WO2019157531A1 (fr) 2018-02-12 2019-08-15 Ionis Pharmaceuticals, Inc. Composés modifiés et leurs utilisations
WO2021030778A1 (fr) 2019-08-15 2021-02-18 Ionis Pharmaceuticals, Inc. Composés oligomères modifiés par liaison et leurs utilisations
WO2022063782A1 (fr) * 2020-09-22 2022-03-31 Astrazeneca Ab Méthode de traitement d'une stéatose hépatique
WO2022135615A1 (fr) * 2020-12-22 2022-06-30 纳肽得有限公司 Petits brins interférents courts de nucléotides pour le traitement de cicatrices et de chéloïdes prolifératifs

Patent Citations (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
US4845205A (en) 1985-01-08 1989-07-04 Institut Pasteur 2,N6 -disubstituted and 2,N6 -trisubstituted adenosine-3'-phosphoramidites
US5552540A (en) 1987-06-24 1996-09-03 Howard Florey Institute Of Experimental Physiology And Medicine Nucleoside derivatives
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5859221A (en) 1990-01-11 1999-01-12 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5587470A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. 3-deazapurines
US6166199A (en) 1990-01-11 2000-12-26 Isis Pharmaceuticals, Inc N-2 substituted purines
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5457191A (en) 1990-01-11 1995-10-10 Isis Pharmaceuticals, Inc. 3-deazapurines
US6531584B1 (en) 1990-01-11 2003-03-11 Isis Pharmaceuticals, Inc. 2'modified oligonucleotides
US5808027A (en) 1990-01-11 1998-09-15 Isis Pharmaceuticals, Inc. N-2 substituted purines in oligonucleotides
US5750692A (en) 1990-01-11 1998-05-12 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5587469A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides containing N-2 substituted purines
US5614617A (en) 1990-07-27 1997-03-25 Isis Pharmaceuticals, Inc. Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5948903A (en) 1991-01-11 1999-09-07 Isis Pharmaceuticals, Inc. Synthesis of 3-deazapurines
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5830653A (en) 1991-11-26 1998-11-03 Gilead Sciences, Inc. Methods of using oligomers containing modified pyrimidines
US5645985A (en) 1991-11-26 1997-07-08 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5763588A (en) 1993-09-17 1998-06-09 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US6005096A (en) 1993-09-17 1999-12-21 Gilead Sciences, Inc. Pyrimidine derivatives
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5811534A (en) 1994-02-01 1998-09-22 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US6005087A (en) 1995-06-06 1999-12-21 Isis Pharmaceuticals, Inc. 2'-modified oligonucleotides
US5994517A (en) 1995-11-22 1999-11-30 Paul O. P. Ts'o Ligands to enhance cellular uptake of biomolecules
US6660720B2 (en) 1998-06-16 2003-12-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US6300319B1 (en) 1998-06-16 2001-10-09 Isis Pharmaceuticals, Inc. Targeted oligonucleotide conjugates
US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use
US7262177B2 (en) 2000-12-01 2007-08-28 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and methods of use
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US20030175906A1 (en) 2001-07-03 2003-09-18 Muthiah Manoharan Nuclease resistant chimeric oligonucleotides
US20030158403A1 (en) 2001-07-03 2003-08-21 Isis Pharmaceuticals, Inc. Nuclease resistant chimeric oligonucleotides
WO2004076639A2 (fr) * 2003-02-26 2004-09-10 Wyeth Compositions et methodes destinees a diagnostiquer et traiter des maladies auto-immunes
US7723509B2 (en) 2003-04-17 2010-05-25 Alnylam Pharmaceuticals IRNA agents with biocleavable tethers
US7875733B2 (en) 2003-09-18 2011-01-25 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation
US7939677B2 (en) 2003-09-18 2011-05-10 Isis Pharmaceuticals, Inc. Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation
US20060148740A1 (en) 2005-01-05 2006-07-06 Prosensa B.V. Mannose-6-phosphate receptor mediated gene transfer into muscle cells
WO2008101157A1 (fr) 2007-02-15 2008-08-21 Isis Pharmaceuticals, Inc. Nucléosides modifiés 5'-substitués-2'-f et composés oligomères préparés à partir de ceux-ci
US20130011922A1 (en) 2007-03-02 2013-01-10 F/K/A Mdrna, Inc. Nucleic acid compounds for inhibiting gene expression and uses thereof
US8314227B2 (en) 2007-05-22 2012-11-20 Marina Biotech, Inc. Hydroxymethyl substituted RNA oligonucleotides and RNA complexes
US20130096289A1 (en) 2007-05-22 2013-04-18 Marina Biotech, Inc. Hydroxymethyl substituted rna oligonucleotides and rna complexes
US9005906B2 (en) 2007-08-15 2015-04-14 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8088904B2 (en) 2007-08-15 2012-01-03 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8796437B2 (en) 2007-08-15 2014-08-05 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8440803B2 (en) 2007-08-15 2013-05-14 Isis Pharmaceuticals, Inc. Tetrahydropyran nucleic acid analogs
US8106022B2 (en) 2007-12-04 2012-01-31 Alnylam Pharmaceuticals, Inc. Carbohydrate conjugates as delivery agents for oligonucleotides
WO2009111658A2 (fr) * 2008-03-05 2009-09-11 Alnylam Pharmaceuticals, Inc. Compositions et procédés pour inhiber l’expression des gènes eg5 et vegf
US20110123520A1 (en) 2008-04-11 2011-05-26 Alnylam Pharmaceuticals, Inc. Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components
US20110313020A1 (en) 2008-12-03 2011-12-22 Marina Biotech, Inc. UsiRNA Complexes
US20130203836A1 (en) 2010-04-01 2013-08-08 Isis Pharmaceuticals, Inc. 2' and 5' modified monomers and oligonucleotides
WO2011133876A2 (fr) 2010-04-22 2011-10-27 Alnylam Pharmaceuticals, Inc. Oligonucléotides comprenant des nucléosides acycliques et abasiques, et analogues
WO2012037254A1 (fr) 2010-09-15 2012-03-22 Alnylam Pharmaceuticals, Inc. Agents à base d'arni modifiés
WO2013033230A1 (fr) 2011-08-29 2013-03-07 Isis Pharmaceuticals, Inc. Complexes oligomère-conjugué et leur utilisation
WO2014179620A1 (fr) 2013-05-01 2014-11-06 Isis Pharmaceuticals, Inc. Composés antisens conjugués et leur utilisation
WO2015106128A2 (fr) 2014-01-09 2015-07-16 Alnylam Pharmaceuticals, Inc. Agents d'arni modifiés
WO2017015555A1 (fr) 2015-07-22 2017-01-26 Wave Life Sciences Ltd. Compositions d'oligonucléotides et procédés associés
WO2019157531A1 (fr) 2018-02-12 2019-08-15 Ionis Pharmaceuticals, Inc. Composés modifiés et leurs utilisations
WO2021030778A1 (fr) 2019-08-15 2021-02-18 Ionis Pharmaceuticals, Inc. Composés oligomères modifiés par liaison et leurs utilisations
WO2022063782A1 (fr) * 2020-09-22 2022-03-31 Astrazeneca Ab Méthode de traitement d'une stéatose hépatique
WO2022135615A1 (fr) * 2020-12-22 2022-06-30 纳肽得有限公司 Petits brins interférents courts de nucléotides pour le traitement de cicatrices et de chéloïdes prolifératifs

Non-Patent Citations (42)

* Cited by examiner, † Cited by third party
Title
ALTERMAN ET AL., NATURE BIOTECH., vol. 37, 2019, pages 844 - 894
BIESSEN ET AL., J. MED. CHEM., vol. 38, 1995, pages 1846 - 1852
CROOKE ET AL., J. PHARMACOL. EXP. THER., vol. 277, 1996, pages 923 - 937
DATABASE Geneseq [online] 11 August 2005 (2005-08-11), "Human lupus-related siRNA antisense strand #4687.", XP002812853, retrieved from EBI accession no. GSN:AEA90750 Database accession no. AEA90750 *
DATABASE Geneseq [online] 11 August 2005 (2005-08-11), "Human lupus-related siRNA sense strand #4687.", XP002812852, retrieved from EBI accession no. GSN:AEA90749 Database accession no. AEA90749 *
ENGLISCH ET AL., ANGEWANDTE CHEMIE, vol. 30, 1991, pages 613
GAUTSCHI ET AL., J. NATL. CANCER INST., vol. 93, March 2001 (2001-03-01), pages 463 - 471
HASHIMOTO ET AL., J. GASTROENTEROL., vol. 46, no. 1, 2011, pages 63 - 69
JIN LINGLI ET AL.: "PSD3 is an oncogene that promotes proliferation, migration, invasion, and G1/S transition while inhibits apoptotic in papillary thyroid cancer", JOURNAL OF CANCER, vol. 12, no. 18, 1 January 2021 (2021-01-01), AU, pages 5413 - 5422, XP093237797, ISSN: 1837-9664, DOI: 10.7150/jca.60885 *
KABANOV ET AL., FEBS LETT., vol. 259, 1990, pages 327 - 330
KOTRONEN ET AL., ARTERIOSCLER THROMB. VASC. BIOL., vol. 28, 2008, pages 27 - 38
KUMAR ET AL., ORG. BIOMOL. CHEM., vol. 11, 2013, pages 5853 - 5865
LEE ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 19, 2011, pages 2494 - 2500
LETSINGER ET AL., PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 6553 - 6556
LEUMANN. CJ., BIOORG. & MED. CHEM., vol. 10, 2002, pages 841 - 854
MAHERDOLNICK, NUC. ACID. RES., vol. 16, 1988, pages 3341 - 3358
MAIER ET AL.: "Synthesis of Antisense Oligonucleotides Conjugated to a Multivalent Carbohydrate Cluster for Cellular Targeting", BIOCONJUGATE CHEMISTRY, vol. 14, 2003, pages 18 - 29, XP002510288, DOI: 10.1021/bc020028v
MANOHARAN ET AL., ANN. N.Y. ACAD. SCI., vol. 660, 1992, pages 306 - 309
MANOHARAN ET AL., BIOORG. ALED. CHEM. LETT., vol. 3, 1993, pages 2765 - 2770
MANOHARAN ET AL., BIOORG. MED. CHEM. LETT., 1994, pages 1053 - 1060
MANOHARAN ET AL., NUCLEOSIDES & NUCLEOTIDES, vol. 14, 1995, pages 969 - 973
MANOHARAN ET AL., TETRAHEDRON LETT., vol. 36, 1995, pages 3651 - 3654
MISHRA ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1264, 1995, pages 229 - 237
NATURE METABOLISM, vol. 4, 2022, pages 60 - 75
NIELSEN ET AL., SCIENCE, vol. 254, 1991, pages 1497 - 1500
NISHINA ET AL., MOLECULAR THERAPY NUCLEIC ACIDS, vol. 4, 2015, pages e220
NISHINA ET AL., MOLECULAR THERAPY, vol. 16, 2008, pages 734 - 740
OBERHAUSER ET AL., NUCL. ACIDS RES., vol. 20, 1992, pages 533 - 538
OKA ET AL., J4CS, vol. 125, 2003, pages 8307
RENSEN ET AL., J. BIOL. CHEM., vol. 276, 2001, pages 37577 - 37584
RENSEN ET AL., J. MED. CHEM., vol. 7, 2004, pages 5798 - 5808
RENSEN ET AL.: "Design and Synthesis of Novel N-Acetylgalactosamine-Terminated Glycolipids for Targeting of Lipoproteins to the Hepatic Asiaglycoprotein Receptor", J. MED. CHEM., vol. 47, 2004, pages 5798 - 5808, XP002551237, DOI: 10.1021/jm049481d
SAISON-BEHMOARAS ET AL., EMBO J., vol. 10, 1991, pages 1111 - 1118
SANGHVI, Y.S.: "Crooke", 1993, CRC PRESS,, article "Antisense Research and Applications", pages: 273 - 288
SANYAL, HEPATOL. RES., vol. 41, 2011, pages 670 - 4
SHATZKES ET AL., SCIENTIFIC REPORTS, vol. 4, 1 April 2014 (2014-04-01), pages 4659, Retrieved from the Internet <URL:doi:10.1038/srep04659>
SHEA ET AL., NUCL. ACIDS RES., vol. 18, 1990, pages 3777 - 3783
SLIEDREGT ET AL., J. MED. CHEM., vol. 42, 1999, pages 609 - 618
SVINARCHUK ET AL., BIOCHIMIE, vol. 75, 1993, pages 49 - 54
VALENTIJN ET AL., TETRAHEDRON, vol. 53, 1997, pages 759 - 770
WAN ET AL., NUC. ACID. RES., vol. 42, 2014, pages 13456
WOOLF ET AL., PROC. NATL. ACAD. SCI. USA, vol. 89, 1992, pages 7305 - 7309

Also Published As

Publication number Publication date
GB202314724D0 (en) 2023-11-08

Similar Documents

Publication Publication Date Title
TWI843738B (zh) 用於減少atxn2表現之化合物及方法
JP7557469B2 (ja) Ａｐｐの発現を低減するための化合物及び方法
TWI856973B (zh) Pnpla3表現之調節劑
IL289789B2 (en) Compounds and methods for lowering tau expression
TWI841564B (zh) Ａｐｏｌ１表現之調節劑
WO2022246251A2 (fr) Composés pour moduler l&#39;expression d&#39;unc13a
TW201819397A (zh) 減少atxn3表現之化合物及方法
CN113728104B (zh) 用于调节ube3a-ats的化合物和方法
JP2020511155A (ja) Ｐｃｓｋ９発現のモジュレーター
EP4206213A1 (fr) Composés et procédés de modulation de smn2
JP2024504377A (ja) Ｄｕｘ４の発現を低減するための化合物及び方法
EP4192476A2 (fr) Composés et procédés de modulation de scn2a
CA3088522A1 (fr) Modulateurs de l&#39;expression de dnm2
CN117106778A (zh) 用于降低kcnt1表达的化合物和方法
JP2024540537A (ja) プログラニュリン発現を調節するための化合物及び方法
CN117597442A (zh) 用于降低pln表达的化合物和方法
CN115335522A (zh) 用于降低apoe表达的化合物和方法
CN116096380A (zh) 调节atxn1的化合物和方法
WO2025068896A1 (fr) Composés et méthodes pour réduire l&#39;expression de psd3
CA3205040A1 (fr) Composes et methodes pour moduler le facteur xii
JP2023544162A (ja) Ｃｈｍｐ７を調節するための化合物
CN116096899A (zh) 调节plp1的化合物和方法
WO2023122681A2 (fr) Composés et méthodes pour réduire l&#39;expression de pcdh19
EP4426837A2 (fr) Composés et méthodes pour réduire l&#39;expression de psd3
WO2025030064A1 (fr) Composés et procédés de réduction de l&#39;expression de tubb4a

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24790708

Country of ref document: EP

Kind code of ref document: A1