HRP20171813T1 - Pripravci komplementarne komponente c5 irna i postupci njihove uporabe - Google Patents

Pripravci komplementarne komponente c5 irna i postupci njihove uporabe Download PDF

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HRP20171813T1
HRP20171813T1 HRP20171813TT HRP20171813T HRP20171813T1 HR P20171813 T1 HRP20171813 T1 HR P20171813T1 HR P20171813T T HRP20171813T T HR P20171813TT HR P20171813 T HRP20171813 T HR P20171813T HR P20171813 T1 HRP20171813 T1 HR P20171813T1
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Croatia
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dsrna agent
nucleotide
dsrna
seq
agent according
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HRP20171813TT
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Kevin Fitzgerald
James Butler
Brian Bettencourt
Anna Borodovsky
Satyanarayana Kuchimanchi
Klaus CHARISSE
Muthiah Manoharan
Martin Maier
Kallanthottathil G. Rajeev
Donald Foster
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Alnylam Pharmaceuticals, Inc.
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Publication of HRP20171813T1 publication Critical patent/HRP20171813T1/hr

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Claims (21)

1. dsRNA sredstvo (dvostruka uzvojnica ribonukleinske kiseline) pogodno za inhibiranje ekspresije komplementarne komponente C5, naznačeno time da navedena dsRNA sadrži sense uzvojnicu i antisense uzvojnicu, te antisense uzvojnica sadrži regiju komplementarnosti koja sadrži barem 15 susjednih nukleotida iz nukleotidne sekvence SEQ ID NO:113.
2. dsRNA sredstvo prema zahtjevu 1, naznačeno time da regija komplementarnosti obuhvaća nukleotidnu sekvencu od SEQ ID NO:113.
3. dsRNA sredstvo prema zahtjevu 1, naznačeno time da sense i antisense lanci obuhvaćaju odgovarajuće nukleotidne sekvence od SEQ ID NO:62 i SEQ ID NO:113.
4. dsRNA sredstvo prema bilo kojem od zahtjeva 1-3, naznačeno time da navedena dsRNA sadrži barem jedan modificirani nukleotid, proizvoljno pri čemu svi nukleotidi sense lanca i svi nukleotidi antisense lanca sadrže modifikaciju.
5. dsRNA sredstvo prema zahtjevu 4, naznačeno time da je barem jedan od navedenih modificiranih nukleotida odabran iz skupine koja se sastoji od 3'-terminalnog kraja deoksi-timin (dT) nukleotida, 2'-O-metil modificiranog nukleotida, 2'-fluoro modificiranog nukleotida, 2'-deoksi-modificiranog nukleotida, zaključanog nukleotida, abazičnog nukleotida, 2'-amino-modificiranog nukleotida, 2'-alkil-modificiranog nukleotida, morfolino nukleotida, fosforamidata, ne-prirodne baze koja sadrži nukleotid, nukleotida koji sadrži 5'-fosforotioatnu skupinu, i terminalnog nukleotida vezanog na derivat kolesterila ili bisdecilamidnu skupinu dodekanske kiseline.
6. dsRNA sredstvo prema zahtjevu 5, naznačeno time da navedeni modificirani nukleotidi sadrže kratku sekvencu 3'-terminalnog kraja deoksi-timin nukleotida (dT).
7. dsRNA sredstvo prema bilo kojem od zahtjeva 1-6, naznačeno time da su uglavnom svi nukleotidi sense uzvojnice i/ili antisense uzvojnice modificirani nukleotidi odabrani iz skupine koja se sastoji od 2'-O-metil modifikacije, 2'-fluoro modifikacije i 3'-terminalnog kraja deoksi-timin (dT) nukleotida.
8. dsRNA sredstvo prema bilo kojem od zahtjeva 1-7, naznačeno time da (a) regija komplementarnosti je duljine barem 17 nukleotida, proizvoljno između 19 i 21 nukleotida duljine, te nadalje proizvoljno duljine od 19 nukleotida; (b) svaka uzvojnica ima duljinu od ne više od 30 nukleotida; (c) barem jedna uzvojnica sadrži 3' privjesak od barem 1 nukleotida, proizvoljno barem 2 nukleotida; i/ili (d) pri čemu navedena antisense uzvojnica sadrži barem 16, 17, 18, 19, ili 20 susjednih nukleotida iz nukleotidne sekvence SEQ ID NO:113 i pri čemu se navedeno dsRNA sredstvo razlikuje u svojoj sposobnosti da inhibira ekspresiju C5 gena za ne više od oko 5, 10, 15, 20, 25, ili 30 % inhibicije od dsRNA koja sadrži cijelu sekvencu.
9. dsRNA sredstvo prema bilo kojem od zahtjeva 1-8 naznačeno time da nadalje sadrži ligand, pri čemu je ligand proizvoljno konjugiran na 3' kraj sense lanca dsRNA sredstva, pri čemu je nadalje proizvoljno ligand derivat N-acetilgalaktozamina (GalNAc).
10. dsRNA sredstvo prema zahtjevu 9, naznačeno time da ligand je [image] pri čemu je dsRNA sredstvo proizvoljno konjugirano na ligand kao što je prikazano u sljedećoj shemi [image] i, pri čemu X je O ili S; poželjno O.
11. dsRNA sredstvo prema bilo kojem od zahtjeva 1-10, naznačeno time da je dsRNA sredstvo odabrano iz skupine koju čine AD-58123 (SEQ ID NO: 122 i 173), AD-58643 (SEQ ID NO: 2873 i 2886), AD-62510 (SEQ ID NO: 2875 i 2888), AD-62643 (SEQ ID NO: 2876 i 2889), AD-62645 (SEQ ID NO: 2878 i 2891), AD-62646 (SEQ ID NO: 2879 i 2892), AD-62650 (SEQ ID NO: 2884 i 2897), i AD-62651 (SEQ ID NO: 2885 i 2898).
12. dsRNA sredstvo prema bilo kojem od zahtjeva 1-11, naznačeno time da sense uzvojnica sadrži dvije fosforotioatne internukleotidne veze na 5'-terminalnom kraju i/ili antisense uzvojnica sadrži dvije fosforotioatne internukleotidne veze na 5'-terminalnom kraju i dvije fosforotioatne internukleotidne veze na 3'-terminalnom kraju.
13. Vektor koji kodira barem jednu uzvojnicu dsRNA sredstva prema bilo kojem od prethodnih zahtjeva, naznačen time da navedena dsRNA ima duljinu od 30 osnovnih parova ili manje, te pri čemu navedeno dsRNA sredstvo cilja navedenu mRNA radi cijepanja.
14. Stanica naznačena time da sadrži dsRNA sredstvo prema bilo kojem od zahtjeva 1-12 ili vektor prema zahtjevu 13.
15. Farmaceutski pripravak naznačen time da je pogodan za inhibiranje ekspresije komplementarne komponente C5 gena koji sadrži dsRNA sredstvo prema bilo kojem od zahtjeva 1-12.
16. Farmaceutski pripravak prema zahtjevu 15, naznačen time da je za uporabu u postupku inhibiranja ekspresije komplementarne komponente C5 gena, pri čemu proizvoljno u navedenom postupku RNAi sredstvo se daje u nepuferiranoj otopini, pri čemu nadalje proizvoljno navedena nepuferirana otopina je fiziološka otopina ili voda.
17. Farmaceutski pripravak za uporabu prema zahtjevu 16, naznačen time da se navedeno RNAi sredstvo primjenjuje s puferskom otopinom, pri čemu proizvoljno navedena puferska otopina sadrži acetat, citrat, prolamin, karbonat, ili fosfat ili bilo koju njihovu kombinaciju, pri čemu poželjno navedena puferska otopina je puferirana fiziološka otopina (PBS).
18. Farmaceutski pripravak naznačen time da sadrži dsRNA sredstvo prema bilo kojem od zahtjeva 1-12 i formulaciju lipida, pri čemu proizvoljno formulacija lipida sadrži LNP, i/ili MC3.
19. In vitro postupak inhibicije komplementarne komponente C5 ekspresije u stanici, te je postupak naznačen time da sadrži: (a) dovođenje u kontakt stanice sa dsRNA sredstvom prema bilo kojem od zahtjeva 1-12 ili farmaceutskim pripravkom prema bilo kojem od zahtjeva 15-18; i (b) održavanje stanice dobivene u koraku (a) tijekom vremena koje je dovoljno za postizanje degradacije transkripta mRNA komplementarne komponente C5 gena, te se tako inhibira ekspresija komplementarne komponente C5 gena u stanici, pri čemu se proizvoljno komplementarna komponenta C5 ekspresije inhibira za barem oko 30%, oko 40%, oko 50%, oko 60%, oko 70%, oko 80%, oko 90%, oko 95%, oko 98% ili oko 100%.
20. dsRNA sredstvo prema bilo kojem od zahtjeva 1-12 naznačeno time da je za uporabu u postupku liječenja subjekta koji ima bolest ili poremećaj koji bi imao koristi od smanjenja ekspresije komplementarne komponente C5, ili sprječavanja barem jednog simptoma kod navedenog subjekta, pri čemu postupak obuhvaća davanje subjektu terapeutski ili profilaktički učinkovite količine dsRNA sredstva ili farmaceutskog pripravka prema bilo kojem zahtjevu 15-18, čime se liječi navedeni subjekt ili se time sprječava barem jedan simptom kod subjekta, pri čemu proizvoljno subjekt je čovjek, te pri čemu nadalje proizvoljno (a) primjena dsRNA na subjekta uzrokuje smanjenje intravaskularne hemolize, stabilizaciju razine hemoglobina i/ili smanjenje C5 proteina, ili (b) poremećaj je bolest povezana s komplementarnom komponentom C5, pri čemu nadalje proizvoljno bolest povezana s komplementarnom komponentom C5 je odabrana iz skupine koju čine paroksizmalna noćna hemoglobinurija (PNH), atipični hemolitičko uremijski sindrom (aHUS), astma, reumatoidni artritis (RA); sindrom antifosfolipidnog protutijela; lupus nefritis; ishemijska-reperfuzijska ozljeda; tipični ili infektivni hemolitičko uremijski sindrom (tHUS); bolest gustih depozita (DDD); optički neuromijelitis (NMO); multifokalna motorna neuropatija (MMN); multipla skleroza (MS); makularna degeneracija (npr., makularna degeneracija povezana sa starošću (AMD)); hemoliza, povišeni jetreni enzimi, i sindrom sniženih trombocita (HELLP); trombotična trombocitopenična purpura (TTP); spontani gubitak fetusa; Pauci-imuni vaskulitis; bulozna epidermoliza; ponavljajući gubitak fetusa; preeklampsija, traumatska ozljeda mozga, mijastenija gravis, bolest hladnih aglutinina, dermatomiozitis bulozni pemfigoid, hemolitičko uremijski sindrom povezan sa Shiga toksinom E. coli, C3 nefropatija, vaskulitis povezan s antineutrofilnim citoplazmatskim protutijelima, humoralno i vaskularno odbacivanje transplantata, disfunkcija transplantata, infarkt miokarda, alogeni transplantat, sepsa, koronarna arterijska bolest, dermatomiozitis, Gravesova bolest, ateroskleroza, Alzheimerova bolest, sindrom sistemskog upalnog odgovora, septički šok, ozljeda leđne moždine, glomerulonefritis, Hashimotov tiroiditis, dijabetes tip I, psorijaza, pemfigus, autoimuna hemolitička anemija (AIHA), ITP, Goodpastureov sindrom, Degosova bolest, antifosfolipidni sindrom (APS), katastrofalni APS (CAPS), kardiovaskularni poremećaj, miokarditis, cerebrovaskularni poremećaj, periferni vaskularni poremećaj, renovaskularni poremećaj, mezenterični/enterični vaskularni poremećaj, vaskulitis, Henoch-Schönleinova purpura nefritis, vaskulitis povezan sa sistemskim eritemskim lupusom, vaskulitis povezan sa reumatoidnim artritisom, imuni kompleksni vaskulitis, Takayasuova bolest, dilatirajuća kardiomiopatija, dijabetička angiopatija, Kawasakijeva bolest (arteritis), venska plinska embolija (VGE), i restenoza nakon postavljanja stenta, rotacijska aterektomija, membranska nefropatija, sindrom Guillain-Barre, i perkutana transluminalna koronarna angioplastika (PTCA), pri čemu poželjno bolest povezana s komplementarnom komponentom C5 je paroksizmalna noćna hemoglobinurija (PNH) ili atipični hemolitički uremijski sindrom (aHUS).
21. dsRNA za uporabu prema zahtjevu 20, naznačena time da (a) postupak dodatno obuhvaća davanje protutijela anti-komplementarne komponente C5, ili njegovog fragmenta koji veže antigen, subjektu; i/ili (b) dsRNA sredstvo se daje u dozi od oko 0.01 mg/kg do oko 10 mg/kg ili oko 0.5 mg/kg do oko 50 mg/kg, pri čemu po izboru (i) dsRNA sredstvo se daje u dozi od oko 10 mg/kg do oko 30 mg/kg, ili u dozi odabranoj iz skupine koja sadrži 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 10 mg/kg, i 30 mg/kg; (ii) dsRNA sredstvo se daje subjektu jednom tjedno; (iii) dsRNA sredstvo se daje subjektu dva puta tjedno; (iv) dsRNA sredstvo se daje subjektu dva puta mjesečno; ili (v) dsRNA sredstvo se daje subjektu jednom mjesečno; i/ili (c) dsRNA sredstvo se daje subjektu potkožno.
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