DK2850186T3 - Sammensætninger og fremgangsmåder til at modulere smn-genfamilie-ekspression - Google Patents

Sammensætninger og fremgangsmåder til at modulere smn-genfamilie-ekspression Download PDF

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DK2850186T3
DK2850186T3 DK13790819.0T DK13790819T DK2850186T3 DK 2850186 T3 DK2850186 T3 DK 2850186T3 DK 13790819 T DK13790819 T DK 13790819T DK 2850186 T3 DK2850186 T3 DK 2850186T3
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oligonucleotide
stranded oligonucleotide
smn2
nucleotides
sequence
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Arthur M Krieg
Romesh Subramanian
James Mcswiggen
Jeannie T Lee
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Massachusetts Gen Hospital
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Claims (19)

1. Enkeltstrenget oligonukleotid med en sekvens 5'-X-Y-Z, hvor X er et hvilket som helst nukleotid, Y er en nukleotidsekvens af 6 nukleotiders længde, der ikke er en seed-sekvens af et humant mikroRNA, og Z er en nukleotidsekvens af 1-23 nukleotiders længde, hvor det enkeltstrengede oligonukleotid er komplementært med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af et SMN-gen, og hvor det enkeltstrengede oligonukleotid aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2.
2. Enkeltstrenget oligonukleotid ifølge krav 1, hvor (a) oligonukleotidet ikke omfatter fire eller flere på hinanden følgende guanosinnukleotider, eventuelt hvor oligonukleotidet ikke omfatter tre eller flere på hinanden følgende guanosinnukleotider; og/eller (b) oligonukleotidet i. er af 8 til 30 nukleotiders længde, eller ii. er af 8 til 10 nukleotiders længde og alle undtagen 1, 2, eller 3 af nukleotiderne af den komplementære sekvens af den PRC2-associerede region er cytosin- eller guanosinnukleotider.
3. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af de foregående krav, hvor mindst et nukleotid af oligonukleotidet er en nukleotidanalog, hvor eventuelt den mindst ene nukleotidanalog resulterer i en forøgelse af Tm af oligonukleotidet i området fra 1 til 5 °C sammenlignet med et oligonukleotid, der ikke har den mindst ene nukleotidanalog.
4. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 3, hvor (a) mindst et nukleotid af oligonukleotidet omfatter en 2' O-methyl, hvor eventuelt (b) hvert nukleotid af oligonukleotidet omfatter en 2' O-methyl.
5. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 3 eller 4(a), hvor (a) oligonukleotidet omfatter mindst et ribonukleotid, mindst et deoxyribonukleotid, eller mindst et broforbundet ("bridged") nukleotid, hvor eventuelt det broforbundne nukleotid er et LNA-nukleotid, et cEt-nukleotid eller et ENA-modificeret nukleotid; eller (b) nukleotiderne af oligonukleotidet omfatter deoxyribonukleotider flankeret af mindst et LNA-nukleotid ved hver af 5'- og 3'-enderne af deoxyribonukleotiderne.
6. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 3, hvor (a) hvert nukleotid af oligonukleotidet er et LNA-nukleotid; eller (b) nukleotiderne af oligonukleotidet omfatter (i) skiftevis deoxyribonukleotider og 2'-fluor-deoxyribonukleotider; (ii) skiftevis deoxyribonukleotider og 2'-O-methylnukleotider; (iii) skiftevis deoxyribonukleotider og ENA-nukleotidanaloger; eller (iv) skiftevis deoxyribonukleotider og LNA-nukleotider; eller (v) skiftevis LNA-nukleotider og 2'-O-methylnukleotider.
7. Enkeltstrenget oligonukleotid ifølge krav 6(b), hvor 5'-nukleotidet af oligonukleotidet er et deoxyribonukleotid eller et LNA-nukleotid.
8. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 7, endvidere omfattende phosphorthioat-internukleotidkoblinger mellem mindst to nukleotider, eventuelt endvidere omfattende phosphorthioat- internukleotidkoblinger mellem alle nukleotider.
9. Enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 8, hvor (a) nukleotidet i 3'-positionen af oligonukleotidet haren 3'-hydroxylgruppe; (b) nukleotidet i 3'-positionen af oligonukleotidet haren 3'-thiophosphat; og/eller (c) oligonukleotidet endvidere omfatter en biotindel konjugeret til 5'-nukleotidet.
10. Enkeltstrenget oligonukleotid omfattende en komplementaritetsregion der er komplementær med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af et SMN-gen, hvor oligonukleotidet aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2, og hvor oligonukleotidet har mindst en af: a) en sekvens der er 5'X-Y-Z, hvor X er et hvilket som helst nukleotid, og hvor X er forankret ved 5'-enden af oligonukleotidet, Y er en nukleotidsekvens af 6 nukleotiders længde, der ikke er en human seed-sekvens af et mikroRNA, og Z er en nukleotidsekvens af 1 til 23 nukleotiders længde; b) en sekvens der ikke omfatter tre eller flere på hinanden følgende guanosinnukleotider; c) en sekvens der har mindre end et tærkselniveau af sekvensidentitet med hver sekvens af nukleotider, med samme længde, der er mellem 50 kilobaser opstrøms fra en 5'-ende af et ikke-målgen og 50 kilobaser nedstrøms fra en 3'-ende af ikke-målgenet; d) en sekvens der er komplementær med en PRC2-associeret region der koder for et RNA, der danner en sekundær struktur omfattende mindst to enkeltstrengede sløjfer; og/eller e) en sekvens der har mere end 60% G-C-indhold; hvor eventuelt i et hvilket som helst af (a)-(e) oligonukleotidet har sekvensen 5'X-Y-Z, og oligonukleotidet er af 8-50 nukleotiders længde.
11. Sammensætning omfattende et enkeltstrenget oligonukleotid ifølge et hvilket som helst af kravene 1 til 10 og en bærer, hvor eventuelt (a) sammensætningen er en farmaceutisk sammensætning omfattende en farmaceutisk acceptabel bærer; (b) sammensætningen omfatter det enkeltstrengede oligonukleotid i en bufferopløsning, og/eller (c) oligonukleotidet er konjugeret til bæreren, hvor eventuelt bæreren er et peptid eller et steroid.
12. Kit omfattende en beholder, der indeholder sammensætningen ifølge krav 11.
13. Fremgangsmåde til forøgelse af ekspression af SMN1 eller SMN2 i en celle, hvilken fremgangsmåde ikke er en fremgangsmåde til behandling af menneskeeller dyrekroppen med kirurgi eller terapi, hvor fremgangsmåden omfatter levering af det enkeltstrengede oligonukleotid ifølge et hvilket som helst af kravene 1 til 10 ind i cellen, hvor eventuelt levering af det enkeltstrengede oligonukleotid ind i cellen resulterer i et niveau af ekspression af SMN1 eller SMN2, der er mindst 50% større end et niveau af ekspression af SMN1 eller SMN2 i en kontrolcelle, der ikke omfatter det enkeltstrengede oligonukleotid.
14. Enkeltstrenget oligonukleotid som defineret i et hvilket som helst af kravene 1-10 til anvendelse i en fremgangsmåde til forøgelse af niveauer af SMN1 eller SMN2 i et individ, hvor fremgangsmåden omfatter indgivelse af det enkeltstrengede oligonukleotid til individet.
15. Enkeltstrenget oligonukleotid som defineret i et hvilket som helst af kravene 1-10 til anvendelse i en fremgangsmåde til behandling afen tilstand associeret med reducerede niveauer af SMN1 eller SMN2 i et individ, hvor fremgangsmåden omfatter indgivelse af det enkeltstrengede oligonukleotid til individet, hvor eventuelt tilstanden er spinal muskelatrofi.
16. In vitro fremgangsmåde til forøgelse af ekspression af SMN-protein i en celle, hvor fremgangsmåden omfatter: levering til cellen af et første enkeltstrenget oligonukleotid komplementært med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af SMN2 og et andet enkeltstrenget oligonukleotid komplementært med en splejsningskontrolsekvens af en mRNA-precursor af SMN2, i mængder der er tilstrækkelige til at forøge ekspression af et modnet mRNA af SMN2, der omfatter exon 7 i cellen, hvor det første enkeltstrengede oligonukleotid aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2, og hvor eventuelt det første enkeltstrengede oligonukleotid er kovalent bundet til det andet enkeltstrengede oligonukleotid gennem en linker.
17. Et første enkeltstrenget oligonukleotid komplementært med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af SMN2, hvor det første enkeltstrengede oligonukleotid aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2, og et andet enkeltstrenget oligonukleotid komplementært med en splejsningskontrolsekvens af en mRNA-precursor af SMN2 til anvendelse i en fremgangsmåde til behandling af spinal muskelatrofi i et individ, hvor fremgangsmåden omfatter: indgivelse til individet af nævnte første og anden enkeltstrengede oligonukleotider i mængder, der er tilstrækkelige til at øge ekspression af SMN-protein i individet.
18. Sammensætning omfattende: et første enkeltstrenget oligonukleotid komplementært med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af SMN2, og et andet enkeltstrenget oligonukleotid komplementært med en splejsningskontrolsekvens af en mRNA-precursor af SMN2, hvor det første enkeltstrengede oligonukleotid aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2, og hvor eventuelt det første enkeltstrengede oligonukleotid er kovalent bundet til det andet enkeltstrengede oligonukleotid gennem en linker.
19. Forbindelse omfattende den generelle formel A-B-C, hvor A er et enkeltstrenget oligonukleotid komplementært med mindst 8 på hinanden følgende nukleotider af en PRC2-associeret region af et gen, hvor det enkeltstrengede oligonukleotid aktiverer eller forstærker ekspression af SMN1 eller SMN2 ved at mindske eller forhindre PRC2-medieret undertrykkelse af SMN1 eller SMN2, B er en linker, og C er et enkeltstrenget oligonukleotid komplementært med en splejsningskontrolsekvens af en mRNA-precursor af genet, hvor genet eventuelt er SMN2.
DK13790819.0T 2012-05-16 2013-05-16 Sammensætninger og fremgangsmåder til at modulere smn-genfamilie-ekspression DK2850186T3 (da)

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