WO2008021136B1 - Methods and sequences to suppress primate huntington gene expression in vivo - Google Patents

Methods and sequences to suppress primate huntington gene expression in vivo

Info

Publication number
WO2008021136B1
WO2008021136B1 PCT/US2007/017638 US2007017638W WO2008021136B1 WO 2008021136 B1 WO2008021136 B1 WO 2008021136B1 US 2007017638 W US2007017638 W US 2007017638W WO 2008021136 B1 WO2008021136 B1 WO 2008021136B1
Authority
WO
WIPO (PCT)
Prior art keywords
nucleic acid
strand
acid duplex
seq
expression
Prior art date
Application number
PCT/US2007/017638
Other languages
French (fr)
Other versions
WO2008021136A2 (en
WO2008021136A3 (en
Inventor
Michael D Kaytor
William F Kaemmerer
Original Assignee
Medtronic Inc
Michael D Kaytor
William F Kaemmerer
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 Medtronic Inc, Michael D Kaytor, William F Kaemmerer filed Critical Medtronic Inc
Priority to JP2009523833A priority Critical patent/JP2010500025A/en
Priority to EP07811178A priority patent/EP2056881A4/en
Publication of WO2008021136A2 publication Critical patent/WO2008021136A2/en
Publication of WO2008021136A3 publication Critical patent/WO2008021136A3/en
Publication of WO2008021136B1 publication Critical patent/WO2008021136B1/en

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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • C12N2310/11—Antisense
    • C12N2310/111—Antisense spanning the whole gene, or a large part of it
    • 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 N.A.
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • 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
    • 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
    • C12N2750/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssDNA viruses
    • C12N2750/00011—Details
    • C12N2750/14011—Parvoviridae
    • C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
    • C12N2750/14171—Demonstrated in vivo effect

Abstract

Disclosed herein are sequences, molecules and methods used to suppress the expression of HD genes encoding for huntingtin protein in primates including Macaca mulatta and Homo sapiens. These sequences, molecules and methods aid in the study of the pathogenesis of HD and can also provide a treatment for this disease by reducing HD mRNA without causing death, locomotor impairment or cellular alterations of the Macaca mulatta and Homo sapiens.

Claims

AMENDED CLAIMS received by the International Bureau on 23 June 2008 (23.06.2008)
1. A method of preventing cytotoxic effects of Huntington's disease ("HD") in a Macaca mulatta or Homo sapiens comprising: introducing into a cell an isolated nucleic acid duplex in an amount sufficient to suppress accumulation of a protein associated with HD, wherein the nucleic acid duplex prevents cytotoxic effects of HD, and wherein the nucleic acid duplex comprises a first strand of nucleic acid and a second strand of nucleic acid, wherein the first strand comprises at least 19 contiguous nucleotides encoded by a member selected from of- the group consisting of SEQ ID NO: 1 and SEQ ID NO: 4, and wherein the second strand is complementary to at least 15 contiguous nucleotides of the first strand, and wherein further the first strand comprising at least 19 contiguous nucleotides encoded by a member of the group consisting of SEQ ID NO: 1 comprises SEQ ID NO: 26.
2. A method of inhibiting expression of huntingtin in a Macaca mulatta or Homo sapiens comprising: introducing into a cell an isolated nucleic acid duplex in an amount sufficient to inhibit expression of huntingtin wherein said nucleic acid duplex inhibits expression of the protein associated with HD, wherein the nucleic acid duplex comprises a first strand of nucleic acid and a second strand of nucleic acid, wherein the first strand comprises at least 19 contiguous nucleotides encoded by a member selected from e£ the group consisting of SEQ ID NO: 1 and SEQ ID NO : 4, and wherein the second strand is complementary to at least 15 contiguous nucleotides of the first strand, and wherein further the first strand
62 comprising at least 19 contiguous nucleotides encoded by a member of the group consisting of SEQ ID NO: 1 comprises SEQ ID NO: 26.
3. The method of claim 1 or 2 , wherein the isolated nucleic acid duplex comprises SEQ. ID. NO: _2J51.
4. The method of claim 1 or 2 , wherein the isolated nucleic acid duplex comprises SEQ. ID. NO: 4.
5. The method of any one of claims 1-4, wherein said isolated nucleic acid duplex is included within a vector.
6. The method of claim 5, wherein the vector is a viral vector.
7. The method of claim 6, wherein the viral vector is the adeno-associated viral (AAV) vector.
8. The method of any one of claims 1-7, wherein said Macaca mulatta or Homo sapiens survive for at least four weeks after the step of introducing the nucleic acid complex .
9. The method of any one of claims 1-8, wherein said Macaca mulatta or Homo sapiens do not exhibit an impairment in fine locomotor activity.
10. The method of any one of claims 1-9, wherein said nucleic acid duplex is introduced into at least one cell located in a brain structure selected from the group consisting of putamen, caudate nucleus, corona radiata, and striatum.
11. The method of claim 10, wherein expression of said nucleic acid duplex does not impair an endoplasmic reticulum of the at least one cell.
63
12. The method of any one of claims 1-11, wherein expression of said nucleic acid duplex does not impair expression or distribution of calnexin.
13. The method of any one of claims 1-12, wherein expression of said nucleic acid duplex does not impair expression or distribution of protein disulfide isomerase (PDI) .
14. The method according to any one of claims 1-13, wherein said nucleic acid duplex is between 19 and 30 base pairs in length.
15. The method according to any one of claims 1-14, wherein said first and/or said second strand of said nucleic acid duplex further comprises an overhang region.
16. The method according to claim 15, wherein said overhang region comprises a 3' overhang region, a 5' overhang region, or both 3' and 5' overhang regions.
17. The method according to claim 15 or 16, wherein said overhang region is from 1 to 10 nucleotides in length.
18. The method according to any one of claims 1-17, wherein said first strand and said second strand of the nucleic acid duplex are operably linked by means of a nucleic acid loop strand to form a hairpin structure comprising a duplex structure and a loop structure.
19. The method according to claim 18, wherein said loop structure contains from 4 to 10 nucleotides.
64
PCT/US2007/017638 2006-08-09 2007-08-08 Methods and sequences to suppress primate huntington gene expression in vivo WO2008021136A2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2009523833A JP2010500025A (en) 2006-08-09 2007-08-08 Methods and sequences for suppressing primate Huntington gene expression in vivo
EP07811178A EP2056881A4 (en) 2006-08-09 2007-08-08 Methods and sequences to suppress primate huntington gene expression in vivo

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11/501,634 2006-08-09
US11/501,634 US7902352B2 (en) 2005-05-06 2006-08-09 Isolated nucleic acid duplex for reducing huntington gene expression

Publications (3)

Publication Number Publication Date
WO2008021136A2 WO2008021136A2 (en) 2008-02-21
WO2008021136A3 WO2008021136A3 (en) 2008-07-03
WO2008021136B1 true WO2008021136B1 (en) 2008-08-07

Family

ID=39082580

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/017638 WO2008021136A2 (en) 2006-08-09 2007-08-08 Methods and sequences to suppress primate huntington gene expression in vivo

Country Status (5)

Country Link
US (1) US7902352B2 (en)
EP (1) EP2056881A4 (en)
JP (1) JP2010500025A (en)
CN (1) CN101557831A (en)
WO (1) WO2008021136A2 (en)

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