DK2344639T3 - Sammensætninger og fremgangsmåder til hæmning af ekspression af transthyretin - Google Patents

Sammensætninger og fremgangsmåder til hæmning af ekspression af transthyretin Download PDF

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DK2344639T3
DK2344639T3 DK09810834.3T DK09810834T DK2344639T3 DK 2344639 T3 DK2344639 T3 DK 2344639T3 DK 09810834 T DK09810834 T DK 09810834T DK 2344639 T3 DK2344639 T3 DK 2344639T3
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dsrna
ttr
nucleotide
expression
seq
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Dinah Wen-Yee Sah
Gregory Hinkle
Rene Alvarez
Stuart Milstein
Qingmin Chen
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Alnylam Pharmaceuticals Inc
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Claims (18)

1. Dobbeltstrenget ribonukleinsyre (dsRNA) til hæmning af ekspression af transthyretin (TTR), hvor dsRNA'et omfatter en sense-streng og en antisense-streng, hvilken antisense-streng omfatter et område, der er komplementært til en del af et mRNA, der koder for transthyretin (TTR), hvor området med komplementaritet er 19 nukleotider langt, antisense-strengen omfatter SEQ ID NO: 170, og hver streng af dsRNA'et er 19, 20, 21, 22, 23 eller 24 nukleotider lang.
2. dsRNA ifølge krav 1, hvor (a) sense-strengen består af SEQ ID NO: 449, og antisense- strengen består af SEQ ID NO: 450; (b) sense-strengen består af SEQ ID NO: 729, og antisense- strengen består af SEQ ID NO: 730; eller (c) sense-strengen består af SEQ ID NO: 1009, og antisense- strengen består af SEQ ID NO: 1010.
3. dsRNA ifølge krav 1, hvor sense-strengen omfatter SEQ ID NO: 169.
4. dsRNA ifølge et hvilket som helst af kravene 1 til 3, hvor dsRNA'et omfatter mindst ét modificeret nukleotid.
5. dsRNA ifølge krav 4, hvor mindst ét af de modificerede nukleotider er udvalgt fra gruppen, der står af: et 2'-0- methylmodificeret nukleotid, et nukleotid, der omfatter en 5'-phosphorthioatgruppe, et terminalt nukleotid, der er koblet til et cholesterylderivat eller en dodekansyrebisdecylamidgruppe, et 2'-deoxy-2'-fluormodificeret nukleotid, et 2'-deoxymodificeret nukleotid, et låst nukleotid, et abasisk nukleotid, et 2'-aminomodificeret nukleotid, et 2'-alkylmodificeret nukleotid, et morpholinnukleotid, et phosphoramidat og et ikke-naturlig base-omfattende nukleotid.
6. dsRNA ifølge et hvilket som helst af kravene 1 til 3, hvor dsRNA'et er konjugeret til en ligand.
7. dsRNA ifølge et hvilket som helst af kravene 1 til 3, hvor dsRNA'et er formuleret i en lipidformulering.
8. Dobbeltstrenget ribonukleinsyre (dsRNA) til hæmning af ekspression af transthyretin (TTR), hvor dsRNA'et omfatter en antisense-streng, der omfatter et område, der er komplementært til 19 nukleotider af nukleotiderne 618-648 i SEQ ID NO: 1331, og hvor antisense-strengen baseparrer med guanin i position 628 i SEQ ID NO: 1331.
9. Vektor, der omfatter en nukleotidsekvens, der koder for begge strenge af dsRNA'et ifølge krav 1 til 8.
10. Celle, (a) der indeholder dsRNA'et ifølge et hvilket som helst af kravene 1 til 8; eller (b) der omfatter vektoren ifølge krav 9.
11. Farmaceutisk præparat til hæmning af ekspression af et TTR-gen, der omfatter dsRNA'et ifølge krav 1 til 8 og et farmaceutisk acceptabelt bæremateriale.
12. Fremgangsmåde til hæmning af TTR-ekspression i en celle, hvilken fremgangsmåde omfatter: (a) etablering af kontakt mellem cellen og dsRNA'et ifølge krav 1 til 8; og (b) opretholdelse af cellen, der er dannet i trin (a) , i tilstrækkelig lang tid til at opnå degradering af mRNA-transkriptet af et TTR-gen til derved hæmning af ekspression af TTR-genet i cellen; forudsat at en hvilken som helst metode til behandling af personens eller dyrets krop ved hjælp af terapi er udelukket.
13. dsRNA ifølge krav 1 til 8 til anvendelse til behandling af en person for en forstyrrelse, der medieres af TTR-ekspression, hvor (a) personen har transthyretin-amyloidose; og/eller (b) personen har en leverforstyrrelse.
14. dsRNA til anvendelse ifølge krav 13, hvor dsRNA'et skal administreres til personen ved ca. 0,01, 0,1, 0,3, 0,5, 1,0, 2,5 eller 5,0 mg/kg.
15. dsRNA til anvendelse ifølge krav 13 eller 14, hvor personen yderligere modtager en terapeutisk metode til behandling af en TTR-amyloidose, hvor den terapeutiske metode er udvalgt fra gruppen, der består af diuretika, inhibitorer af angiotensinomdannende enzym, blokkere af angiotensinreceptor, dialyse eller en levertransplantation.
16. dsRNA til anvendelse ifølge et hvilket som helst af kravene 13 til 15, hvor transthyretin-amyloidose er udvalgt blandt familiær amyloidotisk polyneuropati (FAP), familiær amyloidotisk kardiomyopati (FAC), leptomeningeal/CNS amyloidose, senil systemisk amyloidose (SSA) og senil amyloidose i hjertet (SCA).
17. dsRNA til anvendelse ifølge et hvilket som helst af kravene 13 til 16, hvor dsRNA'et administreres til personen med ikke mere end 1, 2, 3 eller 4 ugers intervaller.
18. dsRNA til anvendelse ifølge et hvilket som helst af kravene 13 til 17, hvor dsRNA'et skal administreres intravenøst eller ved hjælp at intravenøs infusion over 15 minutter.
DK09810834.3T 2008-10-20 2009-10-20 Sammensætninger og fremgangsmåder til hæmning af ekspression af transthyretin DK2344639T3 (da)

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US10695608P 2008-10-20 2008-10-20
US11573808P 2008-11-18 2008-11-18
US15667009P 2009-03-02 2009-03-02
US18554509P 2009-06-09 2009-06-09
US24278309P 2009-09-15 2009-09-15
US24479409P 2009-09-22 2009-09-22
PCT/US2009/061381 WO2010048228A2 (en) 2008-10-20 2009-10-20 Compositions and methods for inhibiting expression of transthyretin

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JP5570806B2 (ja) 2006-05-11 2014-08-13 アルナイラム ファーマシューティカルズ， インコーポレイテッド Ｐｃｓｋ９遺伝子の発現を阻害するための組成物および方法
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