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WO2025160155A1 - Epigenetic targeting of prion diseases - Google Patents

Epigenetic targeting of prion diseases

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Publication number
WO2025160155A1
WO2025160155A1 PCT/US2025/012570 US2025012570W WO2025160155A1 WO 2025160155 A1 WO2025160155 A1 WO 2025160155A1 US 2025012570 W US2025012570 W US 2025012570W WO 2025160155 A1 WO2025160155 A1 WO 2025160155A1
Authority
WO
WIPO (PCT)
Prior art keywords
prnp
gene
epigenetic
editor
orneoceo
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/US2025/012570
Other languages
French (fr)
Inventor
Jonathan Weissman
Eric MINIKEL
Edwin NEUMANN
Tessa BERTOZZI
Sonia VALLABH
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.)
Broad Institute Inc
Whitehead Institute for Biomedical Research
Original Assignee
Broad Institute Inc
Whitehead Institute for Biomedical Research
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 Broad Institute Inc, Whitehead Institute for Biomedical Research filed Critical Broad Institute Inc
Publication of WO2025160155A1 publication Critical patent/WO2025160155A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/22—Ribonucleases [RNase]; Deoxyribonucleases [DNase]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
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    • 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
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    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1003—Transferases (2.) transferring one-carbon groups (2.1)
    • C12N9/1007—Methyltransferases (general) (2.1.1.)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/20—Type of nucleic acid involving clustered regularly interspaced short palindromic repeats [CRISPR]
    • C—CHEMISTRY; METALLURGY
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    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14141—Use of virus, viral particle or viral elements as a vector
    • C12N2750/14143—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

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  • orneoceo - orneoceo: - FEATURE SE IDNO: orneoceo: - "GCSIGNAL":25612566 and25902595 ..,- , , ..,- , - , - , .., ,, , , . . , , , . . , , . - .., ..., - . . , - - . . . «, ⁇ ..,., , ,. doi,., , ,. doi,., ⁇ , ⁇ . ,...,, , . .. -,- ⁇ .
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  • orneoceo - , , , , , , , , , , , , , ,- ,. - , , , , . " , , , , , , , . " , , , , , . , . . , . , , , , , , , , , , , , , , , . , , . , , . , - . --, --, ., . , , , , orneoceo: - -- .. . , . , , , , . . , , , , orneoceo: - -- .. . , . , , , , . . , , , , , orneoceo: - -- .. .
  • orneoceo - . , , - , ., , ⁇ ° . , . , , , , , , , , , - ,,. , , . - , - . , . , . - . _ , _. , . ° , ° ° whil - -, .- . orneoceo: - , --. ...- . ⁇ -° . , ,° . - , -. - , - .° ° - .- ,, . ° , .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Plant Pathology (AREA)
  • Biophysics (AREA)
  • Physics & Mathematics (AREA)
  • Secondary Cells (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

A recombinant prion protein (PRNP) gene-specific epigenetic editor is disclosed, comprising an unmethylated H3K4meO peptide, a DNMT3 methyltransferase-binding domain, and a PRNP gene-specific DNA binding domain. Expression of the epigenetic editor is non-toxic, and effective at silencing prion gene (PRNP) expression through DNA methylation (DNAme) at CpG sites within the PRNP promoter region. The PRNP-specific epigenetic editor should provide an AAV gene therapy approach for the treatment of prion diseases.

Description

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, . , , , ,.,. - . ′ – ,- . - , . - orneoceo: - – - . , , ., , – - ~- ., - , . , , - - . , - --- ,., . , - ,. , . ,–. - - — . , , , , - . . orneoceo: - – - orneoceo: - - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote orneoceo: - Nuceote - uceoe a orneoceo: - uceoe orneoceo: - uceoe orneoceo: - uceoe orneoceo: - uceoe _ orneoceo: - uceoe -- orneoceo: - - ’ , - - , - , , , . ° . - .. . - ′ . - -, . ,- . -. - . . - orneoceo: - . , . , , - , , - . , .. - - -. - , - , - - . . - . . -, . . . - . - ., . - , . , . - . - .. . orneoceo: - - - - , - . , -. . - ,., , - - . ° -, - , - , - , ,, -- , , .. , . - ,., ., , - . .. -~ , -.. - ., - - orneoceo: - - - ,. ° . . , .. - -, . - - ’- - . . -, , , , , ,, , , .′′ . , . . . - . ~ , - . , --- - . - . - , orneoceo: - - . - . .. ,. , - . , , , * - , . - , . . -,- , . , , , . ... - . . . −° , , ,- ... , ~ ,°. , , , . , °. , °. orneoceo: - - . - ° . - . ,- ~ .- - , ,-----.. ,. - , . , --.,. . , , ’ , - . , - , .. , - -,.... , - .. ,- , . . . - ,..., –. .. - -. .. . , , ... - -. - orneoceo: - . , ..., ... ..., . . , . , , , . , ,. , ,- . - . - . . - . , . - . , - .. .. . . . . , - . , - , . - , , . orneoceo: - -, , .- -,--. , . - ′′′ , , ′ , . . ,-. , - . . ,-, . ,-.. , , . °, . , ~ , , ~ , , - , - . , , −° .., , , , - , .-,,, , , , - ,,,, ,, , . , , - ,°. ,. ~. , , orneoceo: - . -, . . , ° −°. - - ° . , , . ,. ° , , . , , , - ° . -- -,, ° . , ,,. , , -, .. , _ , -′ ′- -′ . _ ′- ° . , ’ . - ---, - , . .. , orneoceo: - ,. , , . . - ~ . , --, ,. ., , . , , - ,. ,, - , , , . - ., −° . . . . .. -. , , . . - . - , . . . orneoceo: - . , , , - , ., , −° . , . , , , , , , , - ,,. , , . - , - . , . - . , , . , . - . _ , _. , . ° , ° °...... - -, .- . orneoceo: - , --. ...- . −-° . , , ,° . - , -. - , - .° ° - .- ,, . ° , . , ° . -, . . , ,,- . -. . - ... =, . ’ - ’ - orneoceo: - - . .... - ..... , ........, – .....,.... ,... ,...,–, .. -..–. - ..,. -. ,.. ., . . - . ,– ... ., -.... ,– . . . , .,. . .. - ... ., . ,. -.. . ,– . . .,....,,..,.. ,---.... .., .. .,– .... ,.,– . . -- -- ... ., - .. .., . . . ... .,,– . . - orneoceo: -..,..– .,. . . .. ., . .. ... .,, ,..– – ,. .-. . . ... ....,...., . ,– . ...’ ., - -- . .., – ..... -- - ... ,.,–-. ..-... ..,...,.,– . . - - -. ... ,..., - , ,.. ., – . . ....,...,...,– ,...,. -- - ... ,.. ,.. ,.. , – . . .. , ..,.. , . ., ... , . .. , . --- . ..,,– . ...,.. , ......,..... . ,– orneoceo: -... .,.. ,– .- . . -..’ ., - . . ., –.. . .., ,–. . ...-.-. .. ., . . ., – ... - ., ....., . . .. ., . . -- ..., –... . - ., ,-–. . .....-..... ., ... .,– . . ---...,...,,., .–,.., . --- -. . , .... ., ..., - - – . . -- orneoceo: - .....,.. ,...,–, . . . ... ... ., “-.” -. . ,– . . ...... ..,.. , . .. .,.–, . . -- --_ ..- . - ., – . ... ,.-. -, - .. ....,–., . . - .. .. - - - - . ,– . . . ..., ., . . -- -- .. ’.,.-.., – . . --- .. .,..., . . . ..... ..,.,- . . . . .. .,- - - . .. .. .,– . orneoceo: -.... , -- ...’.,. .,– .. -.... ..,, . . ---- -.. ., .....,,.– . . ..,..,, -. . -- -... ., -....,,– . . --- . ,– . -... ., . .. .., ., – . . .. . . ., –... .,.. ,–., .... .. .,..,.-,-.-, . . ,– ... ., . .,– . ... ,. ,. ,. ,. , , – . . . .... orneoceo: -... ,...,...,,– . ..,... .... .,. .. .,– ....,. ,..,. ,. ,. . , . .. -, .....,......, . - .. .,.,,–,.... --.,- ........, – . . . ....., ., ,– . . . .. , . . ---... ., . ,.–....,. .. ., – . . .... .,. , . . .. ..., .., . -- - .. orneoceo: -..,–., - ..... . . .. .., ..,, . . . . - -- ,--.. ., ...., - - . - - ..... .,.– . ..... .. ,.,- . . -- --...,–., . ... .... . .. .... ,, .,– . ..... . ,– . . . .... .., , –. . ....-...,.. ,.,.. . . ., ..-, – .....,....,,– . . . ......,.,– .-. -- -- orneoceo: -.. .,. ,-–- . . ----.. .,. ,– . -. -. .. .,. ,,–, . . .- -.. ., .. ., -. . -- -.. ......, .,.-- . . -- - .. ., - , - – . . --.. ,., . ,.. ... .... ... . - ., - - .,– . ....., –., . . - ..... . --,– .,. -- - ... ..,.– .., . ... ... ,....,... . ,... , - - ,– . . -- orneoceo: - ....,,–... ., . . . .. ., .. - . , – . . . .. ,. ,..,., . -.. ,– . . .... .., ,–.- . ..... ..., ., . - . ., – . *** , , , . . , . , , ,, .

Claims

orneoceo: - . -, , - -- ., . . , . - , - - ,- ,, - , . ,. , - - - . . - , ... ,- - . .. , - . .. , . .,,,, orneoceo: -. , - . . .-,,-,, . . ., - . - , - - - . . - , - .-- -. . - - , - - ,,, , .- - - -, - . , . .- - . . , - . ', . orneoceo: -. , '- . . , . - -. , , , , .,. , , - , - , , - - , ,, , , , . . ,- -. -
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