HRP20211971T1 - Pripravci i postupci za inhibiciju ekspresije gena hao1 (hidroksikiselina oksidaza 1 (glikolat oksidaza)) - Google Patents

Pripravci i postupci za inhibiciju ekspresije gena hao1 (hidroksikiselina oksidaza 1 (glikolat oksidaza)) Download PDF

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HRP20211971T1
HRP20211971T1 HRP20211971TT HRP20211971T HRP20211971T1 HR P20211971 T1 HRP20211971 T1 HR P20211971T1 HR P20211971T T HRP20211971T T HR P20211971TT HR P20211971 T HRP20211971 T HR P20211971T HR P20211971 T1 HRP20211971 T1 HR P20211971T1
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rnai agent
double
nucleotides
nucleotide
stranded rnai
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HRP20211971TT
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William Querbes
Kevin Fitzgerald
Brian Bettencourt
Abigail LIEBOW
David V. Erbe
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Alnylam Pharmaceuticals, Inc.
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Publication of HRP20211971T1 publication Critical patent/HRP20211971T1/hr

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Claims (20)

1. Dvolančano RNAi sredstvo koje je sposobno inhibirati ekspresiju HAO1 u stanici, naznačeno time što navedeno dvolančano RNAi sredstvo sadrži smisleni lanac i protusmisleni lanac koji tvore dvolančanu regiju, pri čemu navedeni smisleni lanac i navedeni protusmisleni lanac sadrže regiju komplementarnost koja se sastoji od najmanje 15 susjednih nukleotida koji se razlikuju za najviše 3 nukleotida od protusmislene sekvence iz SEQ ID NO:706; pri čemu su uglavnom svi nukleotidi navedenog smislenog lanca i uglavnom svi nukleotidi navedenog protusmislenog lanca modificirani nukleotidi, i pri čemu je navedeni smisleni lanac konjugiran na ligand vezan na 3'-terminalnom kraju.
2. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što su svi nukleotidi navedenog smislenog lanca i svi nukleotidi navedenog protusmislenog lanca modificirani nukleotidi.
3. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1 ili 2, naznačeno time što je najmanje jedan od navedenih modificiranih nukleotida odabran iz skupine koju čine 3'-terminalni deoksi-timidin (dT) nukleotid, 2'-O-metil modificirani nukleotid, 2'-fluoro modificirani nukleotid, 2'-deoksi-modificirani nukleotid, zaključani nukleotid, abazični nukleotid, 2'-amino-modificirani nukleotid, 2'-alkil-modificirani nukleotid, morfolino nukleotid, fosforamidat, neprirodna baza koja sadrži nukleotid, nukleotid koji sadrži 5'-fosforotioatnu skupinu, nukleotid koji sadrži 5' fosfat ili 5' fosfat mimetik, i terminalni nukleotid vezan na derivat kolesterila ili bisdecilamidnu skupinu dodekanske kiseline.
4. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što najmanje jedan lanac sadrži 3' izbočenje od najmanje 1 nukleotida.
5. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što najmanje jedan lanac sadrži 3' izbočenje od najmanje 2 nukleotida.
6. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što ligand je [image]
7. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što navedeno RNAi sredstvo sadrži 6 do 8 fosforotioatnih internukleotidnih veza.
8. Dvolančano RNAi sredstvo prema patentnom zahtjevu 7, naznačeno time što protusmisleni lanac sadrži dvije fosforotioatne internukleotidne veze na 5'-terminalnom kraju i dvije fosforotioatne internukleotidne veze na 3'-terminalnom kraju, a smisleni lanac sadrži najmanje dvije fosforotioatne internukleotidne veze na bilo kojem 5'-terminalnom kraju ili 3'-terminalnom kraju.
9. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što je bazni par na poziciji 1 5'-kraja protusmislenog lanca dupleksa AU bazni par.
10. Dvolančano RNAi sredstvo prema patentnom zahtjevu 1, naznačeno time što RNAi sredstvo je sredstvo koje sadrži sekvencu smislenog lanca gsascuuuCfaUfCfCfuggaaauauaL96 (SEQ ID NO:213) i sekvencu protusmislenog lanca usAfsuauUfuCfCfaggaUfgAfaagucscsa (SEQ ID NO:330) (AD-65585), pri čemu L96 je N-[tris(GalNAc-alkil)-amidodekanoil]-4-hidroksiprolinol (Hyp-(GalNAc-alkil)3), Af je 2'-fluoradenozin-3'-fosfat, Cf je 2'-fluorcitidin-3'-fosfat, Uf je 2'-fluoruridin-3'-fosfat, a je 2'-O-metiladenozin-3'-fosfat, c je 2'-O-metilcitidin-3'-fosfat, g je 2'-O-metilgvanozin-3'-fosfat, u je 2'-O-metiluridin-3'-fosfat i s je fosforotioatna veza.
11. Dvolančano RNAi sredstvo prema bilo kojem od patentnih zahtjeva 1 do 9, pri čemu uglavnom svi nukleotidi navedenog smislenog lanca sadrže modifikaciju odabranu iz skupine koju čine 2'-O-metil modifikacija i 2'-fluoro modifikacija, pri čemu navedeni smisleni lanac sadrži dvije fosforotioatne internukleotidne veze na 5'-terminalnom kraju, pri čemu uglavnom svi nukleotidi navedenog protusmislenog lanca sadrže modifikaciju odabranu iz skupine koju čine 2'-O-metil modifikacija i 2'-fluoro modifikacija, pri čemu navedeni protusmisleni lanac sadrži dvije fosforotioatne internukleotidne veze na 5'-terminalnom kraju i dvije fosforotioatne internukleotidne veze na 3'-terminalnom kraju, i pri čemu je navedeni smisleni lanac konjugiran s jednim ili više GalNAc derivata vezanih preko razgranate dvovalentne ili trovalentne poveznice na 3'-terminalnom kraju.
12. Dvolančano RNAi sredstvo prema patentnom zahtjevu 11 naznačeno time što je za upotrebu u postupku liječenja poremećaja povezanog s HAO1, pri čemu se navedeno RNAi sredstvo daje subkutano subjektu.
13. RNAi sredstvo za upotrebu prema patentnom zahtjevu 12, naznačeno time što svi nukleotidi navedenog smislenog lanca i svi nukleotidi navedenog protusmislenog lanca sadrže modifikaciju.
14. RNAi sredstvo za upotrebu prema patentnom zahtjevu 12, naznačeno time što je subjekt čovjek.
15. RNAi sredstvo za upotrebu prema patentnom zahtjevu 14, naznačeno time što čovjek ima primarnu hiperoksaluriju tipa 1 (PH1).
16. RNAi sredstvo za upotrebu prema patentnom zahtjevu 12, naznačeno time što se dvolančano RNAi sredstvo treba primijeniti u dozi od oko 0.01 mg/kg do oko 10 mg/kg ili oko 1 mg/kg do oko 10 mg/kg.
17. RNAi sredstvo za upotrebu prema patentnom zahtjevu 16, naznačeno time što se dvolančano RNAi sredstvo treba primijeniti u dozi od oko 0.1 mg/kg, oko 1.0 mg/kg, ili oko 3.0 mg/kg.
18. RNAi sredstvo za upotrebu prema patentnom zahtjevu 16, naznačeno time što se navedeno RNAi sredstvo treba primijeniti u dvije ili više doza.
19. RNAi sredstvo za upotrebu prema patentnom zahtjevu 18, naznačeno time što se navedeno RNAi sredstvo treba primijeniti u intervalima odabranim iz skupine koja se sastoji od jednom svakih oko 12 sati, jednom u oko 24 sata, jednom u oko 48 sati, jednom u oko 72 sata , i jednom svakih oko 96 sati.
20. RNAi sredstvo za upotrebu prema patentnom zahtjevu 18, naznačeno time što se navedeno RNAi sredstvo treba primijeniti jednom tjedno do 2 tjedna, do 3 tjedna, do 4 tjedna, do 5 tjedana ili dulje.
HRP20211971TT 2014-10-10 2015-10-09 Pripravci i postupci za inhibiciju ekspresije gena hao1 (hidroksikiselina oksidaza 1 (glikolat oksidaza)) HRP20211971T1 (hr)

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Application Number Priority Date Filing Date Title
US201462062751P 2014-10-10 2014-10-10
US201562147976P 2015-04-15 2015-04-15
US201562214602P 2015-09-04 2015-09-04
PCT/US2015/054881 WO2016057893A1 (en) 2014-10-10 2015-10-09 Compositions and methods for inhibition of hao1 (hydroxyacid oxidase 1 (glycolate oxidase)) gene expression
EP15848512.8A EP3204015B1 (en) 2014-10-10 2015-10-09 Compositions and methods for inhibition of hao1 (hydroxyacid oxidase 1 (glycolate oxidase)) gene expression

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