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WO2013116126A1 - Nouveaux lipides cationiques biodégradables de faible masse moléculaire pour la délivrance d'oligonucléotides - Google Patents

Nouveaux lipides cationiques biodégradables de faible masse moléculaire pour la délivrance d'oligonucléotides Download PDF

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WO2013116126A1
WO2013116126A1 PCT/US2013/023359 US2013023359W WO2013116126A1 WO 2013116126 A1 WO2013116126 A1 WO 2013116126A1 US 2013023359 W US2013023359 W US 2013023359W WO 2013116126 A1 WO2013116126 A1 WO 2013116126A1
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dimethylamino
compound
ethyl
methyl
cyclopropyl
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Steven L. Colletti
Matthew G. Stanton
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L91/00—Compositions of oils, fats or waxes; Compositions of derivatives thereof

Definitions

  • the present invention relates to novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides, to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in vitro and in vivo.
  • Cationic lipids and the use of cationic lipids in lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA have been previously disclosed.
  • Lipid nanoparticles and use of lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA has been previously disclosed.
  • Oligonucleotides (including siRNA and miRNA) and the synthesis of oligonucleotides has been previously disclosed. (See US patent applications: US 2006/0083780, US 2006/0240554, US 2008/0020058, US 2009/0263407 and US 2009/0285881 and PCT patent applications: WO 2009/086558, WO2009/127060,
  • cationic lipids are disclosed in the following patent applications: US 2009/0263407, US 2009/0285881 , US 2010/0055168, US 2010/0055169, US 2010/0063135, US 2010/0076055, US 2010/0099738, US 2010/0104629, WO2010/088537, WO2010/144740, US2010/0324120, US 8,034,376, WO2011/143230, WO2011/000106, US2011/0117125, US2011/0256175, WO2011/141703, WO2011/141704 and WO201 1/141705.
  • cationic lipids such as CLinDMA and DLinDMA have been employed for siRNA delivery to the liver but suffer from non-optimal delivery efficiency along with liver toxicity at higher doses. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver.
  • the present invention employs low molecular weight cationic lipids with one short lipid chain coupled with inclusion of hydrolysable functionality in the lipid chains to enhance the efficiency and tolerability of in vivo delivery of siRNA.
  • the instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver.
  • the present invention employs low molecular weight cationic lipids with one short lipid chain coupled with inclusion of hydrolysable functionality in the lipid chains to enhance the efficiency and tolerability of in vivo delivery of siRNA.
  • the various aspects and embodiments of the invention are directed to the utility of novel cationic lipids useful in lipid nanoparticles to deliver oligonucleotides, in particular, siRNA and miRNA, to any target gene.
  • novel cationic lipids useful in lipid nanoparticles to deliver oligonucleotides, in particular, siRNA and miRNA, to any target gene.
  • WO2010/054384 WO2010/054401, WO2010/054405, WO2010/054406 and WO201 1/153493.
  • WO2010/054384 Rational design of cationic lipids for siRNA delivery, Nature Biotechnology, 2010, 28, 172-176.
  • the cationic lipids of the instant invention are useful components in a lipid nanoparticle for the delivery of oligonucleotides, specifically siRNA and miRNA.
  • R1 and R2 are independently selected from H, (Ci-C6)alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R';
  • R3 is independently selected from (C4-C20)alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R4 is independently selected from (C1 -C16 )alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R5 is independently selected from (C4-C8) alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R6 is independently selected from (C1 -C2 )alkyl, said alkyl optionally substituted with one to three substituents selected from R';
  • R' is independently selected from halogen, R", OR", SR", CN, C0 2 R" or
  • R" is independently selected from H and (Ci-C6)alkyl, wherein said alkyl is optionally substituted with halogen and OH;
  • n 0, 1 , 2, 3, 4 or 5;
  • the invention features a compound having Formula A, wherein:
  • R and R2 are each methyl
  • n 0;
  • R is independently selected from (C-j.-C20)alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R4 is independently selected from (C1 -C16 )alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R5 is independently selected from (C4-C8) alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R6 is independently selected from (C1 -C2 )alkyl, said alkyl optionally substituted with one to three substituents selected from R';
  • Ql and Q2 are each, independently, a bond or -C(0)O, with the proviso that when either Ql or Q2 is a bond then the other is not a bond;
  • the invention features a compound having Formula A, wherein:
  • R1 and R2 are each methyl
  • n 2;
  • R3 is independently selected from (C4-C20)alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R4 is independently selected from (C1 -C16 )alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R5 is independently selected from (C4-C8) alkyl or alkenyl, said alkyl or alkenyl optionally substituted with one to three substituents selected from R';
  • R6 is independently selected from (C1 -C2 )alkyl, said alkyl optionally substituted with one to three substituents selected from R';
  • Ql and Q2 are each, independently, a bond or -C(0)0-, with the proviso that when either Ql or Q2 is a bond then the other is not a bond;
  • Specific cationic lipids are:
  • the cationic lipids disclosed are useful in the preparation of lipid nanoparticles.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of oligonucleotides.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of siRNA and miRNA.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of siRNA.
  • the cationic lipids of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
  • the cationic lipids disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • substituents and substitution patterns on the cationic lipids of the instant invention can be selected by one of ordinary skill in the art to provide cationic lipids that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • Si atoms can be incorporated into the cationic lipids of the instant invention by one of ordinary skill in the art to provide cationic lipids that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of Formula A.
  • different isotopic forms of hydrogen (H) include protium (iH) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within Formula A can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Scheme and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • alkyl means a straight chain, cyclic or branched saturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • alkenyl means a straight chain, cyclic or branched unsaturated aliphatic hydrocarbon having the specified number of carbon atoms including but not limited to diene, triene and tetraene unsaturated aliphatic hydrocarbons.
  • cyclic “alkyl” or “alkenyl” examples include:
  • heterocyclyl or “heterocycle” means a 4- to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, the following: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyri
  • polyamine means compounds having two or more amino groups. Examples include putrescine, cadaverine, spermidine, and spermine.
  • halogen means Br, CI, F and I.
  • Rl and R2 are independently selected from H and (Ci-C6)alkyl, wherein said alkyl is optionally substituted with one to three substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R'.
  • Rl and R2 are independently selected from H, methyl, ethyl and propyl, wherein said methyl, ethyl and propyl are optionally substituted with one to three substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R * .
  • Rl and R2 are independently selected from H, methyl, ethyl and propyl.
  • Rl and R2 are each methyl.
  • R3 is independently selected from: (C4-
  • R3 is independently selected from: (C14-C18) alkenyl.
  • R3 is independently selected from: (Ci6) alkenyl.
  • R3 is independently selected from: (C14) alkenyl. In an embodiment of Formula A, R3 is independently selected from: (Ci6) alkenyl.
  • R3 is independently selected from: ( 3 ⁇ 4-
  • R3 is independently selected from: (C7)alkyl.
  • R4 is independently selected from: (Ci- C 16) alkyl or alkenyl .
  • R4 is independently selected from: (C4-C10) alkenyl.
  • R4 is independently selected from: (C9) alkenyl.
  • R4 is independently selected from: (Q- 1)
  • R4 is independently selected from: (Ci- C2)alkyl.
  • R4 is (C2)alkyl.
  • R4 is (Ci)alkyl.
  • R3 is (C7)alkyl and R4 is (C9)alkenyl.
  • R is (Ci4)alkenyl and R4 is (C2)alkyl.
  • R is (Ci6)alkenyl and R4 is (Ci)alkyl.
  • R5 is independently selected from (C4-C8) alkyl or alkenyl.
  • R5 is independently selected from (C4-C8) alkyl.
  • R5 is independently selected from (C6-C8) alkyl.
  • R5 is (C8)alkyl.
  • R6 is independently selected from (C1-C2) alkyl.
  • R6 is (C2)alkyl. In an embodiment of Formula A, R.6 is (Cl)alkyl.
  • R5 is (Cs)alkyl and R4 is (C2)alkyl.
  • R5 is (Cs)alkyl and R4 is (C])alkyl.
  • R5 is (C7)alkyl and R is (C2)alkyl.
  • R5 is (C7)alkyl and R4 is (Ci)alkyl.
  • Ql and Q2 are each, independently a bond or - C(0)0-, with the proviso that when either Q or Q is a bond then the other is not a bond.
  • R' is R".
  • R" is independently selected from H, methyl, ethyl and propyl, wherein said methyl, ethyl and propyl are optionally substituted with one or more halogen and OH.
  • R" is independently selected from H, methyl, ethyl and propyl.
  • n 0, 1, 2 or 3.
  • n 0, 1 or 2.
  • n 0.
  • n 1
  • n 2
  • heterocyclyl is pyrolidine, piperidine, morpholine, imidazole or piperazine.
  • "monocyclic heterocyclyl” is pyrolidine, piperidine, morpholine, imidazole or piperazine.
  • polyamine is putrescine, cadaverine, spermidine or spermine.
  • alkyl is a straight chain saturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • alkenyl is a straight chain unsaturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • cationic lipids of Formula A include the free form of cationic lipids of Formula A, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some of the isolated specific cationic lipids exemplified herein are the protonated salts of amine cationic lipids.
  • the term "free form" refers to the amine cationic lipids in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the isolated salts exemplified for the specific cationic lipids described herein, but also all the typical pharmaceutically acceptable salts of the free form of cationic lipids of Formula A.
  • the free form of the specific salt cationic lipids described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant cationic lipids can be synthesized from the cationic lipids of this invention which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic cationic lipids are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the cationic lipids of this invention include the conventional non-toxic salts of the cationic lipids of this invention as formed by reacting a basic instant cationic lipids with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic (
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from
  • organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, ⁇ , ⁇ 1 - dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine, betaine caffeine, choline,
  • the cationic lipids of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • Synthesis of the novel cationic lipids is a linear process starting from lipid acid (i). Addition of a lipid based Grignard reagent can generate secondary alcohol (ii). This alcohol is protected as its silyl ether (iii) and the olefin is dihydroxylated with osmium tetroxide to give diol (iv). The diol is oxidatively cleaved with sodium periodate to provide aldehyde (v). The aldehyde is converted to the carboxylic acid containing olefin (vi) by a Wittig olenfination. The acid is converted to the ester (vii) in situ, followed by silyl ether deprotection to give alcohol (viii).
  • the alcohol is oxidized to the ketone (ix) which is further converted to the cyclopropane containing material (x).
  • Either ketone (ix or x) is reductively aminated to give final cationic lipids (xi or xii, respectively).
  • Synthesis of the single carbon homologated cationic lipids xv and xvi is a linear process starting from lipid ketones (ix or x). Conversion of the ketone to the nitrile (xiii or xiv) is accomplished via treatment with TOSMIC and potassium feri-butoxide. Hydrolysis of the nitrile is achieved under acidic conditions to give the primary amide. The amide is selectively reduced to the primary amine and this is reductively aminated to give amines (xv or xvi)
  • Synthesis of two carbon homologated cationic lipids xxi or xxii is a linear process starting from lipid ketone (ix or x). Conversion of the ketone to the ⁇ , ⁇ -unsaturated amide xvii or xviii is accomplished under Peterson conditions. Conjugate reduction of the ⁇ , ⁇ -unsaturation is performed to give amide xix or xx. Chemoselective reduction of the amide could provide final cationic lipids xxi or xxii.
  • Oleyl aldehyde in THF is cooled to 0 °C and treated with nonylmagnesium bromide.
  • the reaction is warmed to room temperature and quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude alcohol ii.
  • the crude product is purified by flash column chromatography.
  • Alcohol ii is taken up in dichloromethane and treated with tri ethyl amine and DMAP. To this solution is added TBDPSC1 in a single portion at ambient temperature. The reaction is quenched with aqueous bicarbonate solution upon completion. The reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude silyl ether iii. The crude product is purified by flash column chromato graphy .
  • Silyl ether iii is taken up in a mixture of tert-butanol, THF and water and treated with osmium tetroxide and NMO.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude diol iv.
  • the crude product is purified by flash column chromatography.
  • Diol iv is taken up in a mixture of THF, dichloromethane, methanol and water and treated with sodium periodate. The reaction is quenched with aqueous bicarbonate solution upon completion. The reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude aldehyde v. The crude product is purified by flash column chromatography.
  • Ylide precursor triphenylphosphinium bromide is taken up in THF and treated with HMPA and lithium hexamethyldisilazide to generate the ylide.
  • aldehyde v Upon reaction completion, the solution is treated with sodium bicarbonate and dimethylsulfate. The reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude ester vii.
  • the crude product is purified by flash column chromatography.
  • Ester vii is taken up in THF and treated with TBAF. The reaction is quenched with aqueous bicarbonate solution upon completion. The reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude alcohol viii. The crude product is purified by flash column chromatography.
  • Alcohol viii is taken up in a mixture of DMSO and dichloromethane and treated with S03- pyridine at ambient temperature. The reaction is quenched with aqueous bicarbonate solution upon completion. The reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude ketone ix. The crude product is purified by flash column chromatography.
  • a solution of ketone ix in THF is treated with dimethylamine, titanium isopropoxide and sodium borohydride.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude amine 1.
  • the crude product is purified by flash column chromatography.
  • a solution of diethylzinc in dichloromethane is cooled to -1 °C and treated drop wise with TFA. After 30 minutes, diiodomethane is added and the resulting solution aged for 30 minutes in an ice bath. To this solution is added ketone ix and the resulting solution is warmed slowly to ambient temperature. The reaction is quenched with aqueous bicarbonate solution upon completion. The reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude cyclopropane x. The crude product is purified by flash column chromatography.
  • Ketone x is carried on to amine 2 as described for compound 1 above.
  • Compounds 3-48 are novel cationic lipids and are prepared according to the
  • a solution of ketone ix is treated with TOSMIC in dimethoxyethane at 0 °C followed by treatment with potassium tert-butoxide.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude nitrile xiii.
  • the crude product is purified by flash column chromatography.
  • a solution of nitrile xiii in methanol is treated with concentrated hydrochloric acid and warmed to reflux.
  • the reaction is evaporated in vacuo upon completion (conversion to primary amide).
  • the crude amide is selectively reduced by dilution in THF and treatment with zinc acetate and triethoxysilane.
  • the reaction is quenched with ammonium chloride solution and partitioned between hexanes and water upon completion.
  • the organics are dried over sodium sulfate, filtered and evaporated in vacuo to give crude primary amine. This material is purified by flash chromatography.
  • the primary amine is taken up in THF and treated with formaldehyde and sodium
  • Amine 50 is prepared from ketone x in a manner analogous to that outlined above for compound
  • Compounds 51 -96 are novel cationic lipids and are prepared according to the
  • the silyl amide Peterson reagent is dissolved in THF and cooled to -63°C. To this solution is added nBuLi. The reaction is warmed to ambient temperature for 30 minutes. The ketone ix is dissolved in THF in a second flask. The ketone solution is transferred to the Peterson reagent over 30 minutes while maintaining the temperature between -60°C and -40°C. The reaction is warmed to -40°C for 1 hour then warmed to 0°C for 30 minutes. The reaction is quenched with sodium bicarbonate, diluted with additional water and partitioned between water/hexanes. The organics is washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give crude , ⁇ -unsaturated amide xvii. The crude product is purified by flash column chromatography.
  • the Copper catalyst is dissolved in toluene under nitrogen. To this is added the PMHS in a single portion. The reaction is aged for 5 minutes. To the solutions are added the ⁇ , ⁇ -unsatured amide xvii. To this mixture, the t-amyl alcohol is added over 3h via syringe pump. After the addition is complete, to the solution is added 20% NH40H to rxn in small portions. Caution: there is a vigorous effervescence and foaming in the beginning of the quench and it should be closely monitored and the ammonium hydroxide added slowly in small portions. The reaction is partitioned between water and hexanes. The organics is filtered through celite and evaporated in vacuo.
  • the resulting rubber solid material is pulverized using a mechanical stirrer in hexanes to give small particulates which is filtered and washed with hexanes.
  • the organics are then evaporated in vacuo and purified by flash chromatography to give amide xix.
  • the amide xix is selectively reduced by dilution in THF and treatment with zinc acetate and triethoxysilane.
  • the reaction is quenched with ammonium chloride solution and partitioned between hexanes and water upon completion.
  • the organics is dried over sodium sulfate, filtered and evaporated in vacuo to give crude amine 97. This material is purified by flash
  • Amine 98 is prepared from ketone x in a manner analogous to that outlined above for compound 97.
  • a solution of acid xxiii and C9-alcohol in DMF is treated with EDCI and diisopropylethylamine.
  • Compound 146 is prepared in a manner analogous to that described above for compound 145 employing the cyclopropanation chemistry as described for compound 2 above.
  • Compounds 147- 162 are novel cationic lipids and are prepared according to General Schemes 1-4 above.
  • a solution of acid xxix in THF is treated with sodium bicarbonate and dimethylsulfate.
  • the solution is warmed to ambient temperature.
  • the reaction is quenched with sodium bicarbonate solution and partitioned between hexanes and water upon completion.
  • the organics are dried over sodium sulfate, filtered and evaporated in vacuo to give crude keto-ester xxx. This material is purified by flash chromatography.
  • Ketone xxx is carried forward to amine 163 in a manner analogous to that described above for compound 1.
  • Ylide precursor triphenylphosphinium bromide is taken up in THF and treated with HMPA and lithium hexamethyldisilazide to generate the ylide.
  • aldehyde xxxv Upon reaction completion, the solution is treated with sodium bicarbonate and dimethylsulfate. The reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude ester xxxvii.
  • the crude product is purified by flash column chromatography.
  • a solution of silyl ether xxxvii in THF is treated with TBAF.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude alcohol.
  • the crude product is purified by flash column chromatography.
  • a solution of alcohol in DMF is treated with pyridinium dichromate.
  • the reaction is quenched with water upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude acid xxxviii.
  • the crude product is purified by flash column chromatography.
  • a solution of acid xxxviii in THF is treated with sodium bicarbonate and dimethyl sulfate.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude diester xxxix.
  • the crude product is purified by flash column chromatography.
  • Ketone xxxix is converted to amine 175 in a manner analogous to that described for compound 1.
  • Diesters similar to compound 175 are prepared wherein modifications to the structure are similar to those outlined in the tables above, i.e. varying lipid chain lengths, methyl and ethyl esters, inclusion of cylcopropanes, modifying position of unsaturation or cyclopropane incorporation, homologation of the dimethylamine headgroup by one or two carbons, and all possible combinations of above.
  • a solution of acid XLVI in dichloromethane is treated with C9 alcohol and EDCI and diisopropylethylamine.
  • the reaction is quenched with aqueous bicarbonate solution upon completion.
  • the reaction mixture is partitioned between water and hexanes, the organics dried over sodium sulfate, filtered and evaporated in vacuo to give crude keto ester XLVII.
  • the crude product is purified by flash column chromatography.
  • Ketone XLVII is converted to amine 176 in a manner analogous to that described for compound 175 above.
  • Diesters similar to compound 176 are prepared wherein modifications to the structure are similar to those outlined in the tables above, i.e. varying lipid chain lengths, methyl and ethyl esters, inclusion of cylcopropanes, modifying position of unsaturation or cyclopropane incorporation, homologation of the dimethylamine headgroup by one or two carbons, and all possible combinations of above.
  • lipid nanoparticle compositions of the instant invention are useful for the delivery of oligonucleotides, specifically siRNA and miRNA:
  • the Lipid Nano-Particles is prepared by an impinging jet process.
  • the particles are formed by mixing lipids dissolved in alcohol with siRNA dissolved in a citrate buffer.
  • the mixing ratio of lipids to siRNA are targeted at 45-55% lipid and 65-45% siRNA.
  • the lipid solution can contain a novel cationic lipid of the instant invention, a helper lipid (cholesterol) , PEG (e.g. PEG-C-DMA, PEG-DMG) lipid, and DSPC at a concentration of 5-15 mg/mL with a target of 9-12 mg/mL in an alcohol (for example ethanol).
  • the ratio of the lipids can have a mole percent range of 25-98 for the cationic lipid with a target of 35-65
  • the helper lipid can have a mole percent range from 0-75 with a target of 30-50
  • the PEG lipid can have a mole percent range from 1-15 with a target of 1-6
  • the DSPC can have a mole precent range of 0-15 with a target of 0-12.
  • the siRNA solution can contain one or more siRNA sequences at a concentration range from 0.3 to 1 .0 mg/mL with a target of 0.3 -0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5.
  • the two liquids are heated to a temperature in the range of 15-40°C, targeting 30-40°C, and then mixed in an impinging jet mixer instantly foraiing the LNP.
  • the teelD can have a range from 0.25 to 1.0 mm and a total flow rate from 10 -600 mL/min.
  • the combination of flow rate and tubing ID can have the effect of controlling the particle size of the LNPs between 30 and 200 nm.
  • the solution can then be mixed with a buffered solution at a higher pH with a mixing ratio in the range of 1 : 1 to 1 :3 vol: vol but targeting 1 :2 vol: vol. This buffered solution is at a temperature in the range of 15-40°C, targeting 30-40°C.
  • the mixed LNPs are held from 30 minutes to 2 hrs prior to an anion exchange filtration step.
  • the temperature during incubating is in the range of 15-40°C, targeting 30-40°C.
  • the solution is filtered through a 0.8 um filter containing an anion exchange separation step.
  • This process can use tubing IDs ranging from 1 mm ID to 5 mm ID and a flow rate from 10 to 2000 mL/min.
  • the LNPs are concentrated and diafiltered via an ultrafiltration process where the alcohol is removed and the citrate buffer is exchanged for the final buffer solution such as phosphate buffered saline.
  • the ultrafiltration process can use a tangential flow filtration format (TFF).
  • This process can use a membrane nominal molecular weight cutoff range from 30 -500 KD.
  • the membrane format is hollow fiber or flat sheet cassette.
  • the TFF processes with the proper molecular weight cutoff can retain the LNP in the retentate and the filtrate or permeate contains the alcohol; citrate buffer; final buffer wastes.
  • the TFF process is a multiple step process with an initial concentration to a siRNA concentration of
  • the LNPs solution is diafiltered against the final buffer for 10 -20 volumes to remove the alcohol and perform buffer exchange. The material can then be concentrated an additional 1 -3 fold.
  • the final steps of the LNP process are to sterile filter the concentrated LNP solution and vial the product.
  • siRNA duplex concentrations are determined by Strong Anion-Exchange High-Performance Liquid Chromatography (SAX-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford MA) with a 2996 PDA detector.
  • the LNPs otherwise referred to as RNAi Delivery Vehicles (RDVs)
  • RDVs RNAi Delivery Vehicles
  • SAX separation using a Dionex BioLC DNAPac PA 200 (4 x 250 mm) column with UV detection at 254 nm.
  • Mobile phase is composed of A: 25 mM NaC10 4 , 10 mM Tris, 20% EtOH, pH 7.0 and B: 250 mM NaC10 4 , 10 mM Tris, 20% EtOH, pH 7.0 with liner gradient from 0-15 min and flow rate of 1 ml/min.
  • the siRNA amount is determined by comparing to the siRNA standard curve.
  • Fluorescence reagent SYBR Gold is employed for RNA quantitation to monitor the encapsulation rate of RDVs.
  • RDVs with or without Triton X-l 00 are used to determine the free siRNA and total siRNA amount.
  • the assay is performed using a SpectraMax M5e microplate spectrophotometer from Molecular Devices (Sunnyvale, CA). Samples are excited at
  • siRNA amount is determined by comparing to the siRNA standard curve.
  • Encapsulation rate (1- free siRNA/total siRNA) xl00%
  • RDVs containing 1 ⁇ g siRNA are diluted to a final volume of 3 ml with 1 x PBS.
  • the particle size and polydispersity of the samples is measured by a dynamic light scattering method using ZetaPALS instrument (Brookhaven Instruments Corporation, Holtsville, NY). The scattered intensity is measured with He-Ne laser at 25°C with a scattering angle of 90°. 4) Zeta Potential analysis
  • RDVs containing 1 ⁇ g siRNA are diluted to a final volume of 2 ml with 1 mM Tris buffer (pH 7.4). Electrophoretic mobility of samples is determined using ZetaPALS instrument (Brookhaven Instruments Corporation, Holtsville, NY) with electrode and He-Ne laser as a light source. The Smoluchowski limit is assumed in the calculation of zeta potentials.
  • lipid concentrations is determined by Reverse Phase High- Performance Liquid Chromatography (RP-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford MA) with a Corona charged aerosol detector (CAD) (ESA Biosciences, Inc, Chelmsford, MA). Individual lipids in RDVs are analyzed using an Agilent Zorbax SB-C18
  • the mobile phase is composed of A: 0.1% TFA in H 2 0 and B: 0.1% TFA in IPA.
  • the gradient can change from 60% mobile phase A and 40% mobile phase B from time 0 to 40% mobile phase A and 60%) mobile phase B at 1.00 min; 40% mobile phase A and 60% mobile phase B from 1.00 to 5.00 min; 40% mobile phase A and 60% mobile phase B from 5.00 min to 25% mobile phase A and 75% mobile phase
  • the individual lipid concentration is determined by comparing to the standard curve with all the lipid components in the RDVs with a quadratic curve fit. The molar percentage of each lipid is calculated based on its molecular weight.
  • Oligonucleotide synthesis is well known in the art. (See US patent applications: US 2006/0083780, US 2006/0240554, US 2008/0020058, US 2009/0263407 and US
  • siRNAs disclosed and utilized in the Examples are synthesized via standard solid phase procedures.
  • LNPs utilizing Compounds 1-176, in the nominal compositions described immediately above, are evaluated for in vivo efficacy.
  • the siRNA can target the mRNA transcript for the firefly (Photinus pyralis) luciferase gene (Accession # Ml 5077).
  • the primary sequence and chemical modification pattern of the luciferase siRNA is displayed above.
  • the in vivo luciferase model employs a transgenic mouse in which the firefly luciferase coding sequence is present in all cells.
  • ROSA26- LoxP-Stop-LoxP-Luc (LSL- Luc) transgenic mice licensed from the Dana Farber Cancer Institute are induced to express the Luciferase gene by first removing the LSL sequence with a recombinant Ad-Cre virus (Vector Biolabs). Due to the organo-tropic nature of the virus, expression is limited to the liver when delivered via tail vein injection. Luciferase expression levels in liver are quantitated by measuring light output, using an IVIS imager (Xenogen) following administration of the luciferin substrate (Caliper Life Sciences). Pre-dose luminescence levels is measured prior to administration of the RDVs.
  • Luciferin in PBS 15mg/mL is intraperitoneally (IP) injected in a volume of 150 ⁇ ⁇ . After a four minute incubation period mice are anesthetized with isoflurane and placed in the IVIS imager. The RDVs (containing siRNA) in PBS vehicle are tail vein injected in a volume of 0.2 mL. Final dose levels can range from 0.1 to 0.5 mg/kg siRNA. PBS vehicle alone is dosed as a control. Mice are imaged 48 hours post dose using the method described above. Changes in luciferin light output directly correlate with luciferase mRNA levels and represent an indirect measure of luciferase siRNA activity. In vivo efficacy results are expressed as % inhibition of luminescence relative to pre-dose luminescence levels. EXAMPLE 2
  • LNPs are incubated at 37°C in 90% rhesus serum at a final LNP concentration of 4ug/mL. Incubation is for 20 minutes with orbital rotation. After incubation, the samples are diluted 1 :20 in PBS and 100 iL of each diluted sample is aliquoted to wells of an anti-PEG antibody coated 96-well plate (Life Diagnostics Cat. No. P-0001PL. After incubation at room temperature for 1 hour, the plate is washed 5X with 300uL PBS. After washing, 50uL of 0.2% Triton X-100 is added to each well and the plate incubated at 37°C for 10 minutes, followed by shaking on a plate shaker for 1 minute at 750 rpm. Samples are frozen prior to performing the ApoE ELISA and stem loop PCR analysis of samples.
  • An ApoE ELISA assay is performed to quantitate ApoE bound to the LNPs after incubation in rhesus serum.
  • Anti-ApoE antibody (Milipore, Cat No. AB947) is diluted 1 : 1000 in PBS and 100 xL of diluted antibody is added to each well of a polystyrene high binding plate. The plate with antibody is incubated overnight at 4°C, after which the plate is washed 2X with 200 ⁇ of PBS. Next, 200 ⁇ of buffer containing 1% BSA and 0.05% Tween-20 in PBS
  • E887-biotin diluted 1 :500 in incubation buffer, is added to each well and incubated for 1 hour at room temperature, followed by a 5X wash with 0.05% Tween-20 in PBS.
  • 100 xL per well, of Streptavidin-HPR (Thermo, Cat. No. TS- 125-HR) is then added and incubated for 1 hour at room temperature.
  • ⁇ of TMB Substrate (Thermo, Cat. No. 34028) is added to each well, followed by incubation at room temperature for 20 minutes in the dark. The colorimetric reaction is stopped with ⁇ of TMB Stop Solution (KPL, Cat. No.
  • An ApoE standard curve is prepared by diluting rhesus Recombinant ApoE in incubation buffer with 0.03%> Triton X-100 with concentrations ranging from 100 ng/mL to 0.78 ng/mL. ApoE standards are evaluated in the ELISA in parallel to the test samples. A rhesus serum only (no LNP) control is utilized to obtain a background subtraction for non-LNP dependent ApoE signal in the ELISA.
  • the amount of siRNA retained in the anti-PEG antibody well is quantitated by stem-loop PCR and related to the number of siRNAs encapsulated per LNP, to give an approximate measure of total LNP particles bound per well.
  • the standard curve is prepared using the molecular weight of the siRNA (13693 g/mol for ApoB 17063) to calculate the copy number.
  • the high standard should contain 10 11 copies per 3 ⁇ 1.
  • a 10-fold serial dilution is performed across a row of an assay plate until the lowest standard contains 10 2 copies per 3 ⁇ 1.
  • Triton lysates from the PEG antibody plate capture is diluted 1 to 2000 in nuclease free water. 10 ⁇ of 'RT-Primer Mix' (Applied Biosystem's TaqMan MicroRNA Reverse Transcription Kit Cat. No. 4366596) is added to each well of a 96-well Micro-Amp QPCR plate (ABI Cat# N801-0560).
  • ApoB RT primer sequence 5' GTCGTATCCAGTGCAGGGTCCGAGGTA
  • ⁇ ⁇ , of each test sample (diluted 1 to 2000) or spiked standard curve (above) is aliquoted into the 96-well plate.
  • the plate is covered with a mat (ABI Cat. No. N801-0550), to minimize evaporation.
  • the plate is briefly centrifuged at 800 rpm for 1 minute.
  • the plate is run on a thermocycler using the following cycling parameters:
  • the RT cycling reaction is composed of ⁇ 0 L test sample, ⁇ ⁇ ⁇ of RT primer mix and 10 ⁇ ., of RT Mix components for a total volume of 3Q ⁇ L.
  • the final concentration of the RT-primer in the total 30 ⁇ , total RT mix is 200nM.
  • the plate is then sealed with the same plate mat, briefly centrifuged at 800 rpm for 1 minute, then run on the thermocycler using the following cycling parameters:
  • the QPCR result is utilized to calculate the siRNA concentration in the PEG antibody capture plate Triton lysates. Based on an estimate of 500 siRNA per LNP particle, the number of LNPs retained in each well of the anti-PEG antibody plate can be calculated. Using the ApoE concentration per well, as determined by the ApoE ELISA and the number of LNP particles per well, an approximate ApoE molecules bound per LNP particle can be calculated.
  • Lipid nanoparticles (LNP) with neutral surface charge are not retained after injection onto heparin sepharose with IX Dulbecco's phosphate buffered saline (DPBS) as the running buffer but elute in the column void volume.
  • Serum apolipoprotein E (ApoE) exhibits high affinity binding with heparin sulfate and it can be shown that LNPs bind to heparin sepharose to an extent dependent on their intrinsic ability to bind ApoE (depending on both lipid nanoparticle composition and ApoE concentration) after incubation with purified and/or recombinant human ApoE or serum samples.
  • Lipid nanoparticles with surface bound ApoE bind to heparin sepharose with high affinity can be eluted only at high salt (1M NaCl).
  • a heparin sepharose binding assay is developed to assess serum ApoE binding to lipid nanoparticles based on the high affinity interaction that ApoE-LNP complexes exhibit toward heparin sepharose.
  • Lipid nanoparticles are incubated at 37°C for 20 min at a final siRNA concentration of 50 ⁇ g/mL with various concentrations of either purified or recombinant human apolipoprotein E or 0.1-50% rat/mouse/rhesus monkey/human serum in IX Dulbecco's phosphate buffered saline (DPBS). After incubation with ApoE or serum LNP samples are diluted 10-fold using IX DPBS and analyzed by heparin sepharose chromatography.
  • DPBS IX Dulbecco's phosphate buffered saline
  • Peak area of retained LNP (after subtraction of appropriate blank signals) is compared to total peak area of LNP control without ApoE and/or serum incubation to determine the percentage of the LNP which undergoes shift to high affinity heparin interaction after incubation with ApoE/serum.
  • a heparin sepharose HI-TRAPTM chromatography column (GE Healthcare; 1 mL bed volume) is equilibrated with either IX or 2X Dulbecco's PBS; the higher 2X salt concentration is used for LNPs with higher intrinsic retention on heparin sepharose (presumably due to higher positive surface charge).
  • LNPs utilizing compounds in the nominal compositions described above are evaluated for in vivo efficacy and increases in alanine amino transferase and aspartate amino transferase in Sprague-Dawley (Crl:CD(SD) female rats (Charles River Labs).
  • the siRNA targets the mRNA transcript for the ApoB gene (Accession # NM 019287).
  • the primary sequence and chemical modification pattern of the ApoB siRNA is displayed above.
  • the RDVs (containing siRNA) in PBS vehicle are tail vein injected in a volume of 1 to 1.5 mL. Infusion rate is approximately 3 ml/min. Five rats are used in each dosing group. After LNP
  • rats are placed in cages with normal diet and water present. Six hours post dose, food is removed from the cages. Animal necropsy is performed 24 hours after LNP dosing. Rats are anesthetized under isoflurane for 5 minutes, then maintained under anesthesia by placing them in nose cones continuing the delivery of isoflurane until ex-sanguination is completed. Blood is collected from the vena cava using a 23 gauge butterfly venipuncture set and aliquoted to serum separator vacutainers for serum chemistry analysis. Punches of the excised caudate liver lobe is taken and placed in RNALater (Ambion) for mRNA analysis.
  • RNALater RNALater
  • liver tissue is homogenized and total RNA isolated using a Qiagen bead mill and the Qiagen miRNA-Easy RNA isolation kit following the manufacturer's instructions. Liver ApoB mRNA levels are determined by quantitative RT-PCR. Message is amplified from purified RNA utilizing a rat
  • ApoB commercial probe set (Applied Biosystems Cat # RN01499054_ml).
  • the PCR reaction is performed on an ABI 7500 instrument with a 96-well Fast Block.
  • the ApoB mRNA level is normalized to the housekeeping PPIB (NM 011149) mRNA.
  • PPIB mRNA levels are determined by RT-PCR using a commercial probe set (Applied Biosytems Cat. No. Mm00478295_ml). Results are expressed as a ratio of ApoB mRNA/ PPIB mRNA. All mRNA data is expressed relative to the PBS control dose.
  • Serum ALT and AST analysis is performed on the Siemens Advia 1800 Clinical Chemistry Analyzer utilizing the Siemens alanine aminotransferase (Cat# 03039631) and aspartate aminotransferase (Cat# 03039631) reagents.
  • Liver tissue is weighed into 20-ml vials and homogenized in 9 v/w of water using a GenoGrinder 2000 (OPS Diagnostics, 1600 strokes/min, 5min). A 50 aliquot of each tissue homogenate is mixed with 300 ⁇ ⁇ of extraction/protein precipitating solvent (50/50 acetonitrile/methanol containing 500 nM internal standard) and the plate is centrifuged to sediment precipitated protein. A volume of 200 ⁇ of each supernatant is then transferred to separate wells of a 96-well plate and 10 ⁇ samples were directly analyzed by LC/MS-MS.
  • OPS Diagnostics 1600 strokes/min, 5min.
  • a 50 aliquot of each tissue homogenate is mixed with 300 ⁇ ⁇ of extraction/protein precipitating solvent (50/50 acetonitrile/methanol containing 500 nM internal standard) and the plate is centrifuged to sediment precipitated protein. A volume of 200 ⁇ of each supernatant is then transferred to separate wells of
  • Standards are prepared by spiking known amounts of a methanol stock solution of compound into untreated rat liver homogenate (9 vol water/weight liver). Aliquots (50 ⁇ ) each standard/liver homogenate is mixed with 300 ⁇ ⁇ of extraction/protein precipitating solvent (50/50 acetonitrile/methanol containing 500 nM internal standard) and the plate is centrifuged to sediment precipitated protein. A volume of 200 ⁇ , of each supernatant is transferred to separate wells of a 96-well plate and 10 ⁇ of each standard is directly analyzed by LC/MS-MS.
  • Absolute quantification versus standards prepared and extracted from liver homogenate is performed using an Aria LX-2 HPLC system (Thermo Scientific) coupled to an API 4000 triple quadrupole mass spectrometer (Applied Biosystems). For each run, a total of 10 ⁇ , sample is injected onto a BDS Hypersil C8 HPLC column (Thermo, 50 x 2mm, 3 ⁇ ) at ambient temperature.
  • LNPs utilizing compounds in the nominal compositions described above are evaluated for in vivo efficacy in male or female Macaca mulatta (rhesus) monkeys.
  • the siRNA targets the mRNA transcript for the ApoB gene (Accession # XM 001097404).
  • the primary sequence and chemical modification pattern of the ApoB siRNA is displayed above.
  • the RDVs (containing siRNA) in PBS vehicle are administered by intravenous injection in the saphenous vein at an injection rate of 20 mL/minute to a dose level of 0.25 mg/kilogram siRNA.
  • the injection volumes are from 1.9 to 2.1 niL/kilogram and monkeys can range in weight from 2.5 to 4.5 kilograms.
  • the RDV or PBS control is administered to three monkeys.
  • liver biopsy samples ( ⁇ 0.5-l gram/sample) are collected from male rhesus monkeys by laparoscopic surgical resection (resection of one biopsy sample from outer edge of one randomly selected liver lobe per monkey). A 5 mm tissue punch is used to sample three non-adjacent ⁇ 50 mg samples from each predose biopsy. Samples are preserved in RNAlaterTM (Ambion) for later CTNNB1 mRNA analysis.
  • liver biopsy samples ( ⁇ 0.5-l gram/sample) are collected from monkeys by laparoscopic surgical resection (2 separate randomly selected liver lobes were resected per monkey). A 5 mm tissue punch is used to sample three non-adjacent ⁇ 50 mg samples per each 48 hr and 168 hr surgical biopsy sample. Samples are preserved in RNAlaterTM (Ambion) for later CTNNBl mRNA analysis.
  • CTNNBl mRNA levels are measured by relative quantitative RT-PCR using a primer/probe set validated for CTNNBl and normalized against mRNA levels of peptidylprolyl isomerase B (also known as PPIB or cyclophilin B) and RNA levels of 18S ribosomal RNA (18S rRNA) .
  • Change in CTNNBl mRNA liver expression are measured as the difference in PCR threshold cycle number (AACt) between post-dose samples and each corresponding monkey's predose liver samples.
  • AACt PCR threshold cycle number
  • mRNA (% knockdown) 100- (100/2 " Ct )
  • ALT Alanine aminotransferase
  • serum that is harvested from clotted monkey whole blood after centrifugation.
  • a Roche Modular System automated chemistry analyzer measures the enzymatic activity of ALT in the serum by using International Federation of Clinical Chemistry standardized procedures and reagents.
  • the analyzer's computer uses absorbance measurements to calculated ALT activity in the sample as compared to a standard curve. The ALT activity is reported in International Units per Liter (IU/L).

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Abstract

La présente invention concerne de nouveaux lipides cationiques qui peuvent être utilisés en combinaison avec d'autres composants lipidiques tels que le cholestérol et les PEG-lipides pour former des nanoparticules lipidiques avec des oligonucléotides. Un objectif de la présente invention consiste à fournir un échafaudage de lipides cationiques qui présente une plus grande efficacité conjointement à une toxicité hépatique inférieure en résultat de niveaux de lipides moins élevés dans le foie. La présente invention utilise des lipides cationiques de faible masse moléculaire avec une chaîne lipidique courte couplés à l'inclusion d'une fonctionnalité hydrolase dans les chaînes lipidiques pour améliorer l'efficacité et la tolérabilité de la délivrance in vivo d'ARNsi.
PCT/US2013/023359 2012-02-01 2013-01-28 Nouveaux lipides cationiques biodégradables de faible masse moléculaire pour la délivrance d'oligonucléotides Ceased WO2013116126A1 (fr)

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