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HRP20200163T1 - Antisens oligomeri i konjugati koji ciljno djeluju na pcsk9 - Google Patents

Antisens oligomeri i konjugati koji ciljno djeluju na pcsk9 Download PDF

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Publication number
HRP20200163T1
HRP20200163T1 HRP20200163TT HRP20200163T HRP20200163T1 HR P20200163 T1 HRP20200163 T1 HR P20200163T1 HR P20200163T T HRP20200163T T HR P20200163TT HR P20200163 T HRP20200163 T HR P20200163T HR P20200163 T1 HRP20200163 T1 HR P20200163T1
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oligomer
antisense oligonucleotide
seq
oligonucleotide conjugate
group
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HRP20200163TT
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Nanna ALBÆK
Maj Hedtjärn
Marie Lindholm
Niels Fisker Nielsen
Andreas Petri
Jacob Ravn
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Roche Innovation Center Copenhagen A/S
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Priority claimed from PCT/EP2013/073858 external-priority patent/WO2014076195A1/en
Application filed by Roche Innovation Center Copenhagen A/S filed Critical Roche Innovation Center Copenhagen A/S
Publication of HRP20200163T1 publication Critical patent/HRP20200163T1/hr

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    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
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    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
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    • C12N2310/30—Chemical structure
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    • C12N2310/341—Gapmers, i.e. of the type ===---===
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Claims (21)

1. Antisens oligonukleotidni konjugat naznačen time što sadrži a. antisens oligomer (A) od između 16 - 22 nukleotida u dužini, koji sadrži neprekidnu sekvencu od 16 nukleotida koji su komplementarni odgovarajućoj dužini SEQ ID NO 31, i pri čemu je navedeni antisens oligomer LNA gapmer, i b. najmanje jedan konjugatni dio koji ciljno djeluje na asijaloglikoproteinski receptor (C) kovalentno pričvršćen za navedeni oligomer (A).
2. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 1, naznačen time što sekvenca antisens oligomera (A) sadrži neprekidnu sekvencu SEQ ID NO 26.
3. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 1, naznačen time što sekvenca antisens oligomera sadrži neprekidnu sekvencu odabranu iz grupe koja se sastoji od SEQ ID NO 2 i SEQ ID NO 3.
4. Antisens oligonukleotidni konjugat u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time što konjugatni dio (C) sadrži N-acetilgalaktozaminski (GalNAc) dio, kao što je mono-valentni, di-valentni, tri-valentni ili tetra-valentni GalNAc dio.
5. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 4, naznačen time što konjugatni dio (C) sadrži tri-valentni GalNAc dio.
6. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 5, naznačen time što je tri-valentni GalNAc dio odabran iz grupe koja se sastoji od Conj 1, 2, 1a i 2a: [image] [image] [image] [image]
7. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 1, koji je odabran iz grupe koja se sastoji od SEQ ID NO 18 i SEQ ID NO 19.
8. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 6, naznačen time što je antisens oligomer (A) konjugiran za konjugatni dio (C) putem linker regiona (B i/ili Y) koji je smješten između neprekidne sekvence oligomera i konjugatnog dijela.
9. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 8, naznačen time što je linker odabran od C6 do C12 amino alkil grupe ili bio-odvojivog fosfat nukleotidnog linkera koji sadrži između 1 do 6 nukleotida.
10. Antisens oligonukleotid u skladu s patentnim zahtjevom 1, naznačen time što neprekidna sekvenca sadrži nukleotidne analoge za povećanje afiniteta.
11. Antisens oligonukleotid u skladu s patentnim zahtjevom 10, naznačen time što su navedeni nukleotidni analozi nukleotidi modifikovani šećerom nezavisno ili zavisno odabrani iz grupe koja se sastoji od 2'-O-alkil-RNK jedinica, 2'-OMe-RNK jedinica, 2'-amino-DNK jedinica, i 2'-fluoro-DNK jedinica.
12. Antisens oligonukleotid u skladu s patentnim zahtjevom 11, naznačen time što oligomer sadrži jednu ili više nukleozidnih veza odabranih iz grupe koja se sastoji od fosforotioata, fosforoditioata i boranofosfata.
13. Antisens oligonukleotidni konjugat u skladu s patentnim zahtjevom 1, naznačen time što se oligonukleotidni konjugat sastoji od SEQ ID NO 18 i SEQ ID NO 19 [image] [image] pri čemu superskript L predstavlja beta-D-oksi LNA jedinicu, MeC predstavlja 5-metilcitozin, subskript s predstavlja fosforotioatnu internukleozidnu vezu, i pri čemu [image] je Conj 2a konjugatni dio koji ciljno djeluje na asijaloglikoproteinski receptor [image]
14. Oligomer od između 16 - 20 nukleotida u dužini, naznačen time što sadrži neprekidnu sekvencu od 16 nukleotida koji su komplementarni odgovarajućoj dužini SEQ ID NO 31, pri čemu je navedeni oligomer LNA gamper.
15. Oligomer prema patentnom zahtjevu 14, naznačen time što neprekidna sekvenca sadrži nukleotidne analoge za povećanje afiniteta nezavisno ili zavisno odabrane iz grupe koja se sastoji od 2'-O-alkil-RNK jedinica, 2'-OMe-RNK jedinica, 2'-amino-DNK jedinica, i 2'-fluoro-DNK jedinica.
16. Oligomer u skladu sa bilo kojim od patentnih zahtjeva 14 do 15, naznačen time što oligomer sadrži jednu ili više nukleozidnih veza odabranih iz grupe koja se sastoji od fosforotioata, fosforoditioata i boranofosfata.
17. Oligomer u skladu sa bilo kojim od patentnih zahtjeva 14 do 16, naznačen time što sadrži neprekidnu sekvencu SEQ ID NO 2 ili SEQ ID NO 3.
18. Farmaceutska kompozicija naznačena time što sadrži oligomer ili antisens oligonukleotidni konjugat u skladu sa bilo kojim od patentnih zahtjeva 1 do 17 i farmaceutski prihvatljiv razblaživač, nosač, sol ili adjuvans.
19. Oligomer ili antisens oligonukleotidni konjugat ili farmaceutska kompozicija u skladu sa bilo kojim od patentnih zahtjeva 1 do 18, za uporabu kao medikament.
20. Oligomer ili antisens oligonukleotidni konjugat ili farmaceutska kompozicija u skladu sa bilo kojim od patentnih zahtjeva 1 do 19 za uporabu u liječenju hiperkolesterolemije ili srodnih poremećaja, kao što je poremećaj odabran iz grupe koja se sastoji od ateroskleroze, hiperlipidemije, hiperkolesterolemije, porodične hiperkolesterolemije, npr. dobivanjem funkcionalnih mutacija u PCSK9, disbalansa HDL/LDL kolesterola, dislipidemija, npr. obiteljska hiperlipidemija (FCHL) ili obiteljska hiperholesterolemija (FHC), stečene hiperlipidemije, hiperkolesterolemije rezistentne na statine, bolesti koronarnih arterija (CAD), i koronarne bolesti srca (CHD).
21. In vitro postupak za inhibiciju PCSK9 u stanici koja eksprimira PCSK9, naznačen time što navedeni postupak sadrži primjenu oligomera ili antisens oligonukleotidnog konjugata ili farmaceutske kompozicije u skladu s bilo kojim od patentnih zahtjeva 1 do 18 navedenoj stanici.
HRP20200163TT 2013-06-27 2020-01-31 Antisens oligomeri i konjugati koji ciljno djeluju na pcsk9 HRP20200163T1 (hr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
EP13174092 2013-06-27
EP13192930 2013-11-14
PCT/EP2013/073858 WO2014076195A1 (en) 2012-11-15 2013-11-14 Oligonucleotide conjugates
EP13192938 2013-11-14
EP14153253 2014-01-30
EP14168331 2014-05-14
EP14739708.7A EP3013959B1 (en) 2013-06-27 2014-06-27 Antisense oligomers and conjugates targeting pcsk9
PCT/EP2014/063757 WO2014207232A1 (en) 2013-06-27 2014-06-27 Antisense oligomers and conjugates targeting pcsk9

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HRP20200163T1 true HRP20200163T1 (hr) 2020-08-07

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