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HRP20200822T1 - Pripravci i postupci za inhibiciju ekspresije gena alas1 - Google Patents

Pripravci i postupci za inhibiciju ekspresije gena alas1 Download PDF

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Publication number
HRP20200822T1
HRP20200822T1 HRP20200822TT HRP20200822T HRP20200822T1 HR P20200822 T1 HRP20200822 T1 HR P20200822T1 HR P20200822T T HRP20200822T T HR P20200822TT HR P20200822 T HRP20200822 T HR P20200822T HR P20200822 T1 HRP20200822 T1 HR P20200822T1
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Croatia
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dsrna
porphyria
optionally
subject
cell
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HRP20200822TT
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Brian Bettencourt
Kevin Fitzgerald
William Querbes
Robert J. Desnick
Makiko YASUDA
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Alnylam Pharmaceuticals, Inc.
Icahn School Of Medicine At Mount Sinai
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Application filed by Alnylam Pharmaceuticals, Inc., Icahn School Of Medicine At Mount Sinai filed Critical Alnylam Pharmaceuticals, Inc.
Publication of HRP20200822T1 publication Critical patent/HRP20200822T1/hr

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Claims (16)

1. Dvolančana ribonukleinska kiselina (dsRNA) za inhibiciju ekspresije ALAS1, pri čemu navedena dsRNA sadrži smisleni lanac i protusmisleni lanac, te protusmisleni lanac sadrži regiju komplementarnosti sa ALAS1 RNA transkriptom (npr., SEQ ID NO:1), koji protusmisleni lanac sadrži usAfsAfGfaUfgAfgAfcAfcUfcUfuUfcUfgsgsu (SEQ ID NO: 4161), pri čemu c, a, g, u = 2'-OMe ribonukleozidi; Af, Cf, Gf, Uf = 2'F ribonukleozidi; s = fosforotioat, ili njihova sekvenca koja se razlikuje za ne više od 1, 2, ili 3 nukleotida.
2. dsRNA prema patentnom zahtjevu 1, naznačena time što nadalje obuhvaća smisleni lanac koji sadrži csasgaaaGfaGfuGfuCfuCfaucuuaL96 (SEQ ID NO: 4160), pri čemu [image]
3. dsRNA prema patentnom zahtjevu 1 ili 2, naznačena time što navedena dsRNA ima jedno ili više sljedećeg: (a) sadrži dupleks regiju koja ima dužinu od 17-23 nukleotidnih parova; (b) najmanje jedan lanac sadrži 3' izbočenje od barem 2 nukleotida; ili (c) svaki lanac nije duži od 26 nukleotida.
4. dsRNA prema patentnom zahtjevu 3, naznačena time što je dupleksna regija dužine 21-23 nukleotidnih parova ili 21 nukleotidni par.
5. dsRNA prema bilo kojem od prethodnih zahtjeva, naznačena time što nadalje sadrži ligand.
6. dsRNA prema patentnom zahtjevu 5, naznačena time što ligand ima jedno ili više od sljedećeg: (a) konjugiran je na 3' kraju smislenog lanca dsRNA; (b) sadrži ugljikohidrat, proizvoljno pri čemu ligand je GalNAc ligand, proizvoljno pri čemu ligand je: [image] (c) je povezan preko dvovalentne ili trovalentne razgranatog poveznice, proizvoljno pri čemu ligand i poveznica su kao što je prikazano u Formuli XXIV: [image] ili (d) cilja dsRNA na hepatocite.
7. dsRNA prema bilo kojem od prethodnih zahtjeva, naznačena time što protusmisleni lanac sadrži ili se sastoji od usAfsAfGfaUfgAfgAfcAfcUfcUfuUfcUfgsgsu (SEQ ID NO: 4161), i/ili smisleni lanac sadrži ili se sastoji od csasgaaaGfaGfuGfuCfuCfaucuuaL96 (SEQ ID NO: 4160).
8. dsRNA prema bilo kojem od prethodnih patentnih zahtjeva, naznačena time što dsRNA ima jedno, dva ili sve sljedeće: (i) kemijski se sintetizira; (ii) ima 3'-izbočenje; ili (iii) sadrži ili se sastoji od smislenog lanca koji sadrži csasgaaaGfaGfuGfuCfuCfaucuuaL96 (SEQ ID NO: 4160) i protusmislenog lanca koji sadrži usAfsAfGfaUfgAfgAfcAfcUfcUfuUfcUfgsgsu (SEQ ID NO: 4161.
9. dsRNA prema patentnom zahtjevu 1, naznačena time što je navedena dsRNA u obliku konjugata koji ima strukturu: [image] ili njegova farmaceutski prihvatljiva sol, pri čemu Af, Cf, Gf, Uf = 2'F ribonukleozidi; Am, Cm, Gm, Um = 2'-OMe ribonukleozidi; [image] = fosforotioat; [image] = fosfodiester, i pri čemu L96 = [image]
10. Stanica naznačena time što sadrži dsRNA prema bilo kojem od zahtjeva 1 do 9.
11. Farmaceutski pripravak naznačen time što sadrži dsRNA prema bilo kojem od zahtjeva 1 do 9, proizvoljno pri čemu pripravak sadrži vodu za injekciju, proizvoljno pri čemu je pripravak pogodan za supkutanu primjenu.
12. dsRNA prema bilo kojem od patentnih zahtjeva 1-9, ili farmaceutski pripravak prema zahtjevu 11, naznačena time što je za uporabu u postupku inhibicije ALAS1 ekspresije u stanici, pri čemu postupak sadrži: (a) unošenje u stanicu dsRNA prema bilo kojem od zahtjeva 1 do 9, ili farmaceutskog pripravka prema zahtjevu 11, i (b) održavanje stanice iz koraka (a) kroz vrijeme dovoljno da se postigne degradacija mRNA transkripta gena ALAS1, čime se inhibira ekspresija gena ALAS1 u stanici, proizvoljno pri čemu se ekspresija ALAS1 inhibira u stanici za najmanje 20% ili najmanje 30%, proizvoljno pri čemu je ekspresija ALAS1 inhibirana u stanici za najmanje 80% mjereno testom razgranate DNA (bDNA).
13. dsRNA prema bilo kojem od patentnih zahtjeva 1-9, ili farmaceutski pripravak prema zahtjevu 11, naznačena time što je za uporabu postupku za smanjenje razine porfirina ili prekursora porfirina (npr., ALA ili PBG) u stanici (npr., hepatocit), koji sadrži dovođenje u kontakt stanice s dsRNA prema bilo kojem od zahtjeva 1 do 9, ili s farmaceutskim pripravkom prema zahtjevu 11, u količini učinkovitoj za smanjenje razine porfirina ili prekursora porfirina u stanici.
14. dsRNA prema bilo kojem od patentnih zahtjeva 1-9, ili farmaceutski pripravak prema zahtjevu 11, naznačena time što je za uporabu za liječenje porfirije kod subjekta, proizvoljno pri čemu porfirija je jetrena porfirija ili akutna intermitentna porfirija (AIP), proizvoljno pri čemu porfirija je akutna jetrena porfirija.
15. dsRNA prema patentnom zahtjevu 7 naznačena time što je za uporabu za liječenje akutne jetrene porfirije.
16. dsRNA, ili farmaceutski pripravak, za uporabu prema patentnom zahtjevu 14 ili 15, naznačen time što upotreba ima jednu ili više od sljedećih značajki: (a) subjekt ima rizik od razvoja ili dijagnosticiranja porfirije; (b) porfirija je akutna intermitentna porfirija ili porfirija s nedostatkom ALA-dehidrataze; (c) (i) dsRNA ili pripravak se primjenjuje nakon akutnog napada porfirije, (ii) dsRNA ili pripravak se primjenjuje tijekom akutnog napada porfirije, ili (iii) dsRNA ili pripravak se primjenjuje profilaktički kako bi se spriječio akutni napad porfirije; (d) dsRNA se primjenjuje dozi od 0.05 do 50 mg/kg tjelesne težine subjekta, npr., u dozi od 0.01 mg/kg do 5 mg/kg tjelesne težine subjekta; (e) postupak (i) smanjuje razinu porfirina ili prekursora porfirina (npr., δ-aminolevulinske kiseline (ALA) ili porfobilinogena (PBG)) kod subjekta, proizvoljno pri čemu je razina smanjena za najmanje 30%, i/ili (ii) inhibira ekspresiju ALAS1 kod subjekta; (f) navedeni postupak (i) ublažava simptom povezan s poremećajem povezanim s ALAS1 (npr., porfirijom), (ii) smanjuje učestalost akutnih napada simptoma povezanih s porfirijom kod subjekta, i/ili (iii) smanjuje učestalost akutnih napada simptoma povezanih s porfirijom kod subjekta kada je subjekt izložen precipitirajućem faktoru; (g) dsRNA ili pripravak koji sadrži dsRNA se primjenjuje prema režimu doziranja, npr., tjedno, dvotjedno ili mjesečno; (h) dsRNA se primjenjuje prije akutnog napada porfirije, npr., tijekom prodroma; (i) subjekt ima povišenu razinu (npr., razinu u plazmi ili urinu) ALA i/ili PBG, i proizvoljno pri čemu subjekt pati od kronične boli; (j) postupak smanjuje povišenu razinu ALA i/ili PBG; (k) postupak smanjuje ili sprječava bol, neuropatiju, i/ili oštećenje živaca; (l) postupak sprječava akutne napade porfirije; ili (m) dsRNA ili pripravak koji sadrži dsRNA je primjenjuje opetovano.
HRP20200822TT 2013-10-04 2020-05-21 Pripravci i postupci za inhibiciju ekspresije gena alas1 HRP20200822T1 (hr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361887288P 2013-10-04 2013-10-04
US201461983720P 2014-04-24 2014-04-24
EP14800179.5A EP3052628B1 (en) 2013-10-04 2014-10-03 Compositions and methods for inhibiting expression of the alas1 gene
PCT/US2014/059160 WO2015051318A1 (en) 2013-10-04 2014-10-03 Compositions and methods for inhibiting expression of the alas1 gene

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