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DK2895608T3 - Dobbeltstrengede oligonukleotidmolekyler til p53 og fremgangsmåder til anvendelse deraf - Google Patents

Dobbeltstrengede oligonukleotidmolekyler til p53 og fremgangsmåder til anvendelse deraf Download PDF

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DK2895608T3
DK2895608T3 DK13776599.6T DK13776599T DK2895608T3 DK 2895608 T3 DK2895608 T3 DK 2895608T3 DK 13776599 T DK13776599 T DK 13776599T DK 2895608 T3 DK2895608 T3 DK 2895608T3
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nucleic acid
molecule
nucleotide
strand
moiety
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Elena Feinstein
Sharon Avkin-Nachum
Hagar Kalinski
Igor Mett
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Quark Pharmaceuticals Inc
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Claims (15)

1. Dobbeltstrenget nukleinsyremolekyle, der omfatter en sense-streng og en antisense-streng, hvilket molekyle har strukturen: (A) 3’(sense-streng: SEQ ID NO: 19) 5’(antisense-streng: SEQ ID NO: 32) hvor hver af A, C, G, U uafhængigt er et umodificeret ribonukleotid, et modificeret ribonukleotid, et umodificeret deoxyribonukleotid, et modificeret deoxyribonukleotid eller en ikke-konventionel del, der er valgt fra gruppen bestående af et spejlnukleotid, en threosenukleinsyre (TNA), en pyrazolotriazin- (PT) nukleotidanalog og et ribonukleotid forbundet med et tilstødende ribonukleotid med en 2’-5’-internukleotidphosphatbinding; hvor hver “ | ” repræsenterer baseparring mellem antisense- og den tilsvarende sense-streng; hvor hver af Z og Z’ er uafhængigt til stede eller fraværende, men, hvis de er til stede, er afhængigt 1-5 konsekutive nukleotider, 1-5 konsekutive nukleotidanaloger eller 1-5 konsekutive ikke-nukleotiddele eller en kombination deraf, eller en konjugatdel, kovalent bundet ved 3’-terminus af den streng, hvori den er til stede; hvor z” kan være til stede eller fraværende, men, hvis den er til stede, er den en cap-del, eller en konjugatdel kovalent bundet ved 5’-terminus af sense-strengen; og hvor sekvensen af sense-strengen er komplementær til sekvensen af antisense-strengen; forudsat at ikke hvert nukleotid er et deoxyribonukleotid; or et farmaceutisk salt af et sådant molekyle.
2. Molekyle ifølge krav 1, eller et farmaceutisk salt af et sådant molekyle, hvor det modificerede ribonukleotid omfatter en modifikation ved 2’-positionen af sukkerdelen, navnlig hvor det modificerede ribonukleotid er et 2’-O-methylsukker-modificeret ribonukleotid.
3. Molekyle ifølge krav 1 eller 2, eller et farmaceutisk salt af et sådant molekyle, hvor én af eller både Z og Z’ er til stede.
4. Molekyle ifølge krav 3, eller et farmaceutisk salt af et sådant molekyle, hvor hver af Z og Z’ er en 1-2 konsekutiv ikke-nukleotiddel.
5. Molekyle ifølge krav 4, eller et farmaceutisk salt af et sådant molekyle, hvor hver ikke-nukleotiddel er en 1,3-propandiol, mono(dihydrogenphosphat) (C3), der kan være phosphoryleret eller ikke-phosphoryleret, navnlig hvor Z er én C3-ikke-nukleotiddel (C3), der kan være phosphoryleret eller ikke-phosphoryleret; og hvor Z’ er to konsekutive C3-ikke-nukleotiddele (C3-C3), der kan være phosphorylerede eller ikke-phosphorylerede.
6. Molekyle ifølge krav 1, der har en sense-streng og en antisense-streng:
5’ cap-GGGCCUGACUCAGACUGAU-C3-pi 3’(sense-streng; SEQ ID NO: 19) 5’ AUCAGUcUGAGUCAGGCCC-C3-C3 3’(antisense-streng; SEQ ID NO: 32), hvor hver af A, U, G og C er et umodificeret ribonukleotid; hvor hver af U og C er en 2’-O-methylsukker-modificeret ribonukleotid; hvor c er et ribonukleotid forbundet med et tilstødende (5’>3’) med en 2’-5’-internukleotidpho sphatbinding; hvor i antisensestrengen og i sense-strengen, hvert konsekutive ribonukleotid er forbundet med det næste ribonukleotid af en phosphodiesterbinding; hvor sense-strengen omfatter et 1,3-propandiol, mono(dihydrogenphosphat) (C3) non- nukleotidoverhæng kovalent bundet ved 3’-terminus af strengen; hvor sense-strengen omfatter en 5’-cap-z" kovalent bundet ved 5’-terminus af strengen; hvor antisensestrengen omfatter et C3-C3-ikke-nukleotidoverhæng kovalent bundet ved 3’- terminus af strengen; og hvor 3’-terminus af sense-strengen er phosphoryleret (pi); eller et farmaceutisk salt af et sådant molekyle.
7. Molekyle ifølge krav 6, hvor 5’-cap kovalent bundet ved 5’-terminus af sense-strengen er 1,3-propandiol, mono(dihydrogenphosphat) (C3); og hvor i antisensestrengen ribonukleotidet ved 5’-terminus er phosphoryleret (phos) og overhænget ved 3’-terminus er phosphoryleret (-C3-C3-pi); eller et farmaceutisk salt af et sådant molekyle.
8. Molekyle ifølge krav 6, eller et farmaceutisk salt af et sådant molekyle, hvor i antisensestrengen C3-C3 ikke-nukleotido verhænget ko valent bundet ved 3’-terminus af strengen er phosphoryleret (-C3-C3-pi).
9. Molekyle ifølge et hvilket som helst af kravene 1-6, 8, eller et farmaceutisk salt af et sådant molekyle, hvor 5’-cap z" er til stede og er valgt fra gruppen bestående af en abasisk ribosedel, en abasisk deoxyribosedel, en inverteret deoxyribosedel, en inverteret deoxyabasisk del (idAb), amino-C6-del (AM-c6), C6-amino-pi, en ikke-nukleotiddel, navnlig 1,3-propandiol, mono(dihydrogenphosphat) (C3), et spejlnukleotid, en 5,6,7,8-tetrahydro-2-naphthalen-smørsyre-phosphodiester (THNB), og en konjugatdel, såsom en vitamindel eller en lægemiddeldel.
10. Sammensætning, der omfatter molekyle ifølge et hvilket som helst af kravene 1-9 eller et farmaceutisk salt af et sådant molekyle; og en farmaceutisk acceptabel bærer.
11. Molekyle ifølge et hvilket som helst af kravene 1-9, eller et farmaceutisk salt af et sådant molekyle, eller sammensætning ifølge krav 10 til anvendelse i en fremgangsmåde til behandling af et individ, der lider af en sygdom eller forstyrrelse forbundet med en p53-ekspression, hvilken fremgangsmåde omfatter administrering til individet af molekylet eller sammensætningen i en mængde, der er tilstrækkelig til at regulere ekspression af p53.
12. Molekyle, eller farmaceutisk acceptabelt salt af et sådant molekyle, eller sammensætning til anvendelse ifølge krav 11, hvor sygdommen eller forstyrrelsen er valgt fra gruppen bestående af iskæmi-reperfusionslæsion, en hørenedsættelse, en høreforstyrrelser, en balanceforstyrrelse, et høretab, kemoterapi-induceret alopeci, strålingsterapiinduceret alopeci, et akut nyresvigt, en akut nyrelæsion, en kronisk nyresygdom (CKD), en bivirkning forbundet med anti-cancerterapi, forsinket graftfunktion (Delayed Graft Function - DGF) hos en nyretransplantatpatient, en rygmarvslæsion, en hjernelæsion, et epilepsianfald, apopleksi, en neurodegenerativ forstyrrelse, Parkinsons sygdom, Alzheimers sygdom, en tumor, en forbrænding, et sår, hypertermi, hypoxi, iskæmi, organtransplantation, knoglemarvstransplantation (BMT), myokardieinfarkt/hjerteanfald, kardiotoksicitet, en p53-positiv cancer og akut leversvigt.
13. Molekyle ifølge et hvilket som helst af kravene 1-9, eller et farmaceutisk salt af et sådant molekyle, eller en sammensætning, der omfatter et sådant molekyle, eller en sammensætning, der omfatter det farmaceutiske salt af et sådant molekyle, til anvendelse i behandling af en p53-positiv cancer hos et individ, hvor molekylet, eller det farmaceutiske salt af et sådant molekyle, eller sammensætningen, der omfatter et sådant molekyle, eller sammensætningen, der omfatter det farmaceutiske salt af et sådant molekyle, administreres i en mængde til at regulere ekspression af et p53-gen og derved gøre den p53-positive cancer sensitiv over for kemoterapi hos individet.
14. Molekyle ifølge et hvilket som helst af kravene 1-9, eller et farmaceutisk salt af et sådant molekyle, eller en sammensætning, der omfatter et sådant molekyle, eller en sammensætning, der omfatter det farmaceutiske salt af et sådant molekyle, til anvendelse i hæmopoietisk progenitorekspansion eller i stimulering af hæmatopoese.
15. Molekyle ifølge et hvilket som helst af kravene 1-9, eller et farmaceutisk salt af et sådant molekyle, eller en sammensætning, der omfatter et sådant molekyle, eller en sammensætning, der omfatter det farmaceutiske salt af et sådant molekyle, til anvendelse ved returnering af p53-null hæmopoietisk stamcelle (HSC).
DK13776599.6T 2012-09-12 2013-09-12 Dobbeltstrengede oligonukleotidmolekyler til p53 og fremgangsmåder til anvendelse deraf DK2895608T3 (da)

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PCT/US2013/059349 WO2014043292A1 (en) 2012-09-12 2013-09-12 Double-stranded oligonucleotide molecules to p53 and methods of use thereof

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WO2014043292A1 (en) 2014-03-20
ES2704855T3 (es) 2019-03-20
US20190040385A1 (en) 2019-02-07
AU2013315524A1 (en) 2015-02-19
US10781449B2 (en) 2020-09-22

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