DK2164967T3 - Reduktion af off-target-rna-interferenstoksicitet - Google Patents

Reduktion af off-target-rna-interferenstoksicitet Download PDF

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DK2164967T3
DK2164967T3 DK08756453.0T DK08756453T DK2164967T3 DK 2164967 T3 DK2164967 T3 DK 2164967T3 DK 08756453 T DK08756453 T DK 08756453T DK 2164967 T3 DK2164967 T3 DK 2164967T3
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sequence
nucleic acid
expression
rnai
sirna
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Beverly L Davidson
Monteys Alejandro Mas
Ryan Boudreau
Jodi L Mcbride
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Univ Iowa Res Found
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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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    • 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
    • C12N15/111—General methods applicable to biologically active non-coding nucleic acids
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/14—Type of nucleic acid interfering N.A.
    • C12N2310/141—MicroRNAs, miRNAs
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/50—Physical structure
    • C12N2310/53—Physical structure partially self-complementary or closed
    • C12N2310/531—Stem-loop; Hairpin
    • C—CHEMISTRY; METALLURGY
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    • C12N2320/00—Applications; Uses
    • C12N2320/50—Methods for regulating/modulating their activity
    • C12N2320/53—Methods for regulating/modulating their activity reducing unwanted side-effects
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    • C12N2330/00—Production
    • C12N2330/50—Biochemical production, i.e. in a transformed host cell
    • C12N2330/51—Specially adapted vectors

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (19)

1. Nukleinsyre, der koder for et kunstigt primært miRNA-transkript (pri-miRNA), der i rækkefølge efter position består af en 5'-flankerende region, en første siRNA-region, en sløjferegion, en anden siRNA-region og en 3'-flankerende region, hvor den 5'-flankerende region omfatter: (a) en 5'-sammenkædningssekvens, der er fortløbende koblet til den første siRNA-region, hvor 5'-sammenkædningssekvensen består af 5-7 nukleotider, (b) en 5'-udbulingssekvens, der er placeret opstrøms for 5'-sammenkædningssekvensen, der består af 1-10 nukleotider, og (c) en 5'-spacersekvens, der er placeret opstrøms for 5'-udbulingssekvensen, hvor 5'-spacersekvensen er UGGUACCGUU (SEQ ID NO: 180).
2. Nukleinsyre ifølge krav 1, hvor 5'-sammenkædningssekvensen koder for GUGASSS, hvor S er enten et G- eller C-nukleotid, fortrinsvis hvor 5'-sammenkædningssekvensen koder for GUGAGCG.
3. Nukleinsyre ifølge krav 2, hvor 5'-udbulingssekvensen omfatter et kloningssted, fortrinsvis hvor kloningsstedet koder for et Xhol-sted.
4. Nukleinsyre ifølge krav 1, hvor den 5'-flankerende region yderligere omfatter en 5'-opstrømssekvens, der er placeret opstrøms for 5'-spacersekvensen, fortrinsvis hvor 5'-opstrømssekvensen er ca. 30-2000 nukleotider lang.
5. Nukleinsyre ifølge et hvilket som helst af kravene 1 til 4, hvor den 3'-flankerende region omfatter en 3'-sammenkædningssekvens, der er fortløbende koblet til den anden siRNA-region, fortrinsvis hvor 3'-sammenkædningssekvensen består af 5-7 nukleotider, fortrinsvis hvor 3'-sammenkædningssekvensen er mindst ca. 85 % komplementær til 5'-sammenkædningssekvensen, fortrinsvis hvor 3'-sammenkædningssekvensen koder for CGCYUAC, hvor Y er C eller U, fortrinsvis hvor 3'-sammenkædningssekvensen koder for CGCCUAC.
6. Nukleinsyre ifølge krav 5, hvor den 3'-flankerende region yderligere omfatter en 3'-udbulingssekvens, der er placeret nedstrøms for 3'-sammenkædningssekvensen, fortrinsvis hvor 3'-udbulingssekvensen omfatter et kloningssted, fortrinsvis hvor kloningsstedet koder for et Spel/Xbal-sted eller et Spel-sted.
7. Nukleinsyre ifølge krav 2, hvor 5'-udbulingssekvensen koder for UAAACUCGA.
8. Nukleinsyre ifølge krav 6, hvor 3'-udbulingssekvensen består af ca. 1-10 nukleotider, fortrinsvis hvor 3'-udbulingssekvensen koder for UAG.
9. Nukleinsyre ifølge krav 6 eller 8, hvor 5'-udbulingssekvensen er komplementær til 3'-udbulingssekvensen i kun ét nukleotid i hver ende af udbulingssekvensen.
10. Nukleinsyre ifølge et hvilket som helst af kravene 6, 8 eller 9, hvor den 3'-flankerende region yderligere omfatter en 3'-spacersekvens, der er placeret nedstrøms for 3'-udbulingssekvensen, fortrinsvis hvor 3'-spacersekvensen består af 10-12 nukleotider, fortrinsvis hvor 3'-spacersekvensen er AGCGGCCGCCA, fortrinsvis hvor 3'-spacersekvensen er mindst ca. 70 % komplementær til 5'-spacersekvensen.
11. Nukleinsyre ifølge krav 10, hvor den 3'-flankerende region yderligere omfatter en 3'-nedstrømssekvens, der er placeret nedstrøms for 3'-spacersekvensen, fortrinsvis hvor 5'-opstrømssekvensen ikke i signifikant grad matcher med 3'-nedstrømssekvensen, fortrinsvis hvor 3'-nedstrømssekvensen er ca. 30-2000 nukleotider lang.
12. Nukleinsyre ifølge et hvilket som helst af kravene 1-11, hvor sløjferegionen er fra 15-19 nukleotider lang, fortrinsvis hvor sløjferegionen er 17 nukleotider lang.
13. Nukleinsyre ifølge et hvilket som helst af kravene 1-12, hvor sløjferegionen koder for CUNNNNNNNNNNNNNNNGG eller CCNNNNNNNNNNNNNNNGG, fortrinsvis hvor sløjferegionen koder for CUGUGAAGCCACAGAUGGG eller CCGUGAAGCCACAGAUGGG.
14. RNA, der kodes af nukleinsyren ifølge et hvilket som helst af kravene 1-13.
15. Ekspressionskassette, der omfatter en promotor, der er fortløbende koblet til nukleinsyren ifølge et hvilket som helst af kravene 1-13.
16. Vektor, der omfatter ekspressionskassetten ifølge krav 15.
17. Vektor ifølge krav 16, hvor vektoren er en adenoassocieret virus (AAV)-vektor.
18. Nukleinsyre ifølge et hvilket som helst af kravene 1-13, ekspressionskassette ifølge krav 15, vektor ifølge krav 16 eller 17 til anvendelse til terapi, der resulterer i RNA-interferens med lav toksicitet.
19. Nukleinsyre ifølge et hvilket som helst af kravene 1-13, ekspressionskassette ifølge krav 15, vektor ifølge krav 16 eller 17 til anvendelse til behandling af en neurodegenerativ sygdom.
DK08756453.0T 2007-05-31 2008-05-29 Reduktion af off-target-rna-interferenstoksicitet DK2164967T3 (da)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US93246807P 2007-05-31 2007-05-31
US3868508P 2008-03-21 2008-03-21
US7062208P 2008-03-25 2008-03-25
US12/111,025 US20090036395A1 (en) 2007-04-26 2008-04-28 Rna interference suppression of neurodegenerative diseases and methods of use thereof
PCT/US2008/065130 WO2008150897A2 (en) 2007-05-31 2008-05-29 Reduction of off-target rna interference toxicity

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US (4) US8258286B2 (da)
EP (2) EP2164967B1 (da)
AU (4) AU2008260103B2 (da)
CA (1) CA2691617C (da)
DK (1) DK2164967T3 (da)
ES (1) ES2549122T3 (da)
PT (1) PT2164967E (da)
WO (1) WO2008150897A2 (da)

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