HRP20230127T1 - Nukleinske kiseline za inhibiranje ekspresije lpa u stanici - Google Patents
Nukleinske kiseline za inhibiranje ekspresije lpa u stanici Download PDFInfo
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- HRP20230127T1 HRP20230127T1 HRP20230127TT HRP20230127T HRP20230127T1 HR P20230127 T1 HRP20230127 T1 HR P20230127T1 HR P20230127T T HRP20230127T T HR P20230127TT HR P20230127 T HRP20230127 T HR P20230127T HR P20230127 T1 HRP20230127 T1 HR P20230127T1
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- nucleic acid
- structural strand
- acid according
- nucleotides
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- 108020004707 nucleic acids Proteins 0.000 title claims 26
- 150000007523 nucleic acids Chemical class 0.000 title claims 26
- 102000039446 nucleic acids Human genes 0.000 title claims 26
- 230000002401 inhibitory effect Effects 0.000 title claims 2
- 125000003729 nucleotide group Chemical group 0.000 claims 14
- 239000002773 nucleotide Substances 0.000 claims 13
- 239000003446 ligand Substances 0.000 claims 7
- 150000001875 compounds Chemical class 0.000 claims 5
- 230000004048 modification Effects 0.000 claims 4
- 238000012986 modification Methods 0.000 claims 4
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000005647 linker group Chemical group 0.000 claims 3
- 230000007170 pathology Effects 0.000 claims 3
- 102100040214 Apolipoprotein(a) Human genes 0.000 claims 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims 2
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 claims 2
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 claims 2
- OVRNDRQMDRJTHS-KEWYIRBNSA-N N-acetyl-D-galactosamine Chemical group CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-KEWYIRBNSA-N 0.000 claims 2
- 229910019142 PO4 Inorganic materials 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 239000012752 auxiliary agent Substances 0.000 claims 2
- 150000001720 carbohydrates Chemical class 0.000 claims 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 230000000295 complement effect Effects 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- 239000010452 phosphate Substances 0.000 claims 2
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 2
- ZGYYPTJWJBEXBC-QYYRPYCUSA-N (2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1F ZGYYPTJWJBEXBC-QYYRPYCUSA-N 0.000 claims 1
- 101710115418 Apolipoprotein(a) Proteins 0.000 claims 1
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- 208000006011 Stroke Diseases 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 claims 1
- -1 alkylene ether Chemical group 0.000 claims 1
- 206010002906 aortic stenosis Diseases 0.000 claims 1
- 208000029078 coronary artery disease Diseases 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 1
- 239000002502 liposome Substances 0.000 claims 1
- 101150091521 lpa gene Proteins 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000002245 particle Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
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- C12N15/09—Recombinant DNA-technology
- 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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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Claims (15)
1. Nukleinska kiselina za inhibiranje ekspresije LPA u stanici, naznačena time, da sadrži najmanje jednu dupleks regiju koja sadrži barem dio prve strukturne niti i barem dio druge strukturne niti koja je barem djelomično komplementarna prvoj strukturnoj niti, pri čemu je navedena prva strukturna nit barem djelomično komplementarna barem odsječku RNA koja je transkribirana iz LPA gena, gdje navedena prva strukturna nit sadrži nukleotidni slijed SEQ ID NO: 9 i opcionalno gdje navedena druga strukturna nit sadrži nukleotidni slijed SEQ ID NO: 10.
2. Nukleinska kiselina prema patentnom zahtjevu 1, naznačena time, da navedena prva strukturna nit ima duljinu od 19-35 nukleotida i/ili navedena druga strukturna nit ima duljinu od 17-35 nukleotida, opcionalno pritom se barem jedna dupleks regija sastoji od 17-25, poželjno od 19-25, uzastopnih nukleotidnih baznih parova, i nadalje opcionalno pritom nukleinska kiselina:
a) završava tupim krajem na oba kraja; ili
b) ima prevjes na jednom kraju i tupi kraj na drugom; ili
c) ima prevjes na oba kraja.
3. Nukleinska kiselina prema bilo kojem od prethodnih patentnih zahtjeva, naznačena time, da su jedan ili više nukleotida na prvoj i/ili na drugoj strukturnoj niti modificirani, u svrhu tvorbe modificiranih nukleotida.
4. Nukleinska kiselina prema bilo kojem od prethodnih patentnih zahtjeva, naznačena time, da nukleinska kiselina sadrži fosforotioatnu vezu između dva ili tri terminalna 3' nukleotida i/ili 5' nukleotida s jednog ili oba kraja od prve i/ili druge strukturne niti.
5. Nukleinska kiselina prema bilo kojem od prethodnih patentnih zahtjeva, naznačena time, da je nukleinska kiselina konjugirana na ligand.
6. Nukleinska kiselina prema patentnom zahtjevu 5, naznačena time, da ligand sadrži (i) jedan ili više ostataka N-acetil galaktozamin (GalNAc) skupine ili njihovih derivata, i (ii) poveznik, gdje poveznik konjugira najmanje jedan ostatak GalNAc skupine ili njegov derivat na nukleinsku kiselinu.
7. Nukleinska kiselina prema bilo kojem od patentnih zahtjeva 5-6, naznačena time, da nukleinska kiselina koja je konjugirana na ligand, sadrži spoj formule (I):
[S-X1-P-X2]3-A-X3- (I)
u kojoj:
S predstavlja saharid, poželjno gdje saharid je N-acetil galaktozamin;
X1 predstavlja C3-C6 alkilen ili (-CH2-CH2-O)m(-CH2)2- gdje m je 1, 2 ili 3;
P je fosfat ili modificirani fosfat, poželjno tiofosfat;
X2 je alkilen ili alkilen eter formule (-CH2)n-O-CH2- gdje n = 1-6;
A je jedinica grananja;
X3 predstavlja jedinicu premoštenja;
pri čemu je nukleinska kiselina koja je definirana u bilo kojem od patentnih zahtjeva 1 do 3, konjugirana na X3 preko fosfata ili modificiranog fosfata, poželjno tiofosfata.
8. Nukleinska kiselina prema bilo kojem od patentnih zahtjeva 5-6, naznačena time, da prva RNA strukturna nit je spoj formule (X):
[image]
gdje b je 0 ili 1; i
druga RNA strukturna nit je spoj formule (XI):
[image]
u kojoj:
c i d su neovisno 0 ili 1;
Z1 i Z2 su RNA odsječci od prve odnosno druge RNA strukturne niti;
Y je O ili S;
n je 0, 1, 2 ili 3;
L1 je poveznik na kojega je vezan ligand; i
gdje b + c + d je 2 ili 3.
9. Nukleinska kiselina prema patentnom zahtjevu 1, naznačena time, da je nukleinska kiselina konjugirana na ligand i posjeduje sljedeću strukturu:
[image]
u kojoj Z je nukleinska kiselina u skladu s patentnim zahtjevom 1.
10. Nukleinska kiselina prema patentnom zahtjevu 9, naznačena time, da nukleinska kiselina sadrži dvije fosforotioatne veze između svaka od tri terminalna 3' nukleotida i između svaka od tri terminalna 5' nukleotida na prvoj strukturnoj niti, i dvije fosforotioatne veze između tri terminalna nukleotida od kraja 3' od druge strukturne niti i pritom je ligand konjugiran na kraj 5' od druge strukturne niti.
11. Nukleinska kiselina prema patentnom zahtjevu 1, naznačena time, da je nukleinska kiselina konjugirana na ligand, pri čemu prva RNA strukturna nit je spoj formule (XV):
[image]
gdje b je 0 ili 1; i
druga RNA strukturna nit je spoj formule (XVI):
[image]
u kojoj c i d su neovisno 0 ili 1;
pri čemu:
Z1 i Z2 su RNA odsječci od prve odnosno druge RNA strukturne niti;
Y je O ili S;
R1 je H ili metil;
n je 0, 1, 2 ili 3; i
L je isti ili različit u formulama (XV) i (XVI) i bira se iz skupine koja se sastoji od sljedećih:
-(CH2)q, gdje q = 2-12;
-(CH2)r-C(O)-, gdje r = 2-12;
-(CH2-CH2-O)s-CH2-C(O)-, gdje s = 1-5;
-(CH2)t-CO-NH-(CH2)t-NH-C(O)-, gdje t je neovisno 1-5;
-(CH2)u-CO-NH-(CH2)u-C(O)-, gdje u je neovisno 1-5; i
-(CH2)v-NH-C(O)-, gdje v je 2-12; i
pri čemu je terminalni C(O), ako je prisutan, vezan na NH skupinu;
i pritom b + c + d je 2 ili 3.
12. Nukleinska kiselina prema bilo kojem od patentnih zahtjeva 1 ili 9-11, naznačena time, da sadrži slijed i modifikacije kako je prikazano dolje:
[image]
pri čemu su specifične modifikacije predstavljene sa sljedećim brojevima
1=2'F-dU,
2=2'F-dA,
3=2'F-dC,
4=2'F-dG,
5=2'-OMe-rU;
6=2'-OMe-rA;
7=2'-OMe-rC;
8=2'-OMe-rG.
13. Nukleinska kiselina prema bilo kojem od patentnih zahtjeva 1 ili 9-11, naznačena time, da su nukleotidi na pozicijama 2 i 14 od kraja 5' od prve strukturne niti, modificirani s 2' fluoro modifikacijom, dok su nukleotidi na drugoj strukturnoj niti koji odgovaraju poziciji 11, ili 13, ili 11 i 13, ili 11-13 od prve strukturne niti, modificirani s 2' fluoro modifikacijom.
14. Pripravak, naznačen time, da sadrži nukleinsku kiselinu prema bilo kojem od patentnih zahtjeva 1 do 13, i opcionalno, prijenosno sredstvo za raspodjelu i/ili fiziološki prihvatljivo pomoćno sredstvo i/ili nosač i/ili razrjeđivač i/ili pufer i/ili konzervans, pri čemu je za uporabu kao medikament, poželjno za prevenciju ili liječenje ili smanjenje rizika bolesti ili patologije, pri čemu bolest ili patologija je pretpostavljeno kardiovaskularna bolest, dok je kardiovaskularna bolest pretpostavljeno moždani udar, ateroskleroza, tromboza, koronarna srčana bolest ili stenoza aorte i/ili bilo koja druga bolest ili patologija koja je povezana s povišenim razinama čestica koje sadrže Lp(a).
15. Farmaceutski pripravak, naznačen time, da sadrži nukleinsku kiselinu prema bilo kojem od patentnih zahtjeva 1 do 13, i nadalje sadrži prijenosno sredstvo za raspodjelu, poželjno liposome i/ili fiziološki prihvatljivo pomoćno sredstvo i/ili nosač i/ili razrjeđivač.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP17201449.0A EP3483270A1 (en) | 2017-11-13 | 2017-11-13 | Products and compositions |
| EP18179175.7A EP3483271A3 (en) | 2017-11-13 | 2018-06-21 | Products and compositions |
| GB201815915 | 2018-09-28 | ||
| EP18803644.6A EP3710586B1 (en) | 2017-11-13 | 2018-11-13 | Nucleic acids for inhibiting expression of lpa in a cell |
| PCT/EP2018/081106 WO2019092283A1 (en) | 2017-11-13 | 2018-11-13 | Nucleic acids for inhibiting expression of lpa in a cell |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20230127T1 true HRP20230127T1 (hr) | 2023-03-31 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20230127TT HRP20230127T1 (hr) | 2017-11-13 | 2018-11-13 | Nukleinske kiseline za inhibiranje ekspresije lpa u stanici |
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| Country | Link |
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| US (2) | US11319537B2 (hr) |
| EP (2) | EP3710586B1 (hr) |
| JP (1) | JP7245254B2 (hr) |
| KR (1) | KR102553382B1 (hr) |
| CN (1) | CN111465694A (hr) |
| AU (1) | AU2018363840B2 (hr) |
| BR (1) | BR112020009152A2 (hr) |
| CA (1) | CA3081905C (hr) |
| DK (1) | DK3710586T3 (hr) |
| ES (1) | ES2938193T3 (hr) |
| FI (1) | FI3710586T3 (hr) |
| HR (1) | HRP20230127T1 (hr) |
| HU (1) | HUE061265T2 (hr) |
| IL (1) | IL274503A (hr) |
| LT (1) | LT3710586T (hr) |
| MX (1) | MX2020004897A (hr) |
| PL (1) | PL3710586T3 (hr) |
| RS (1) | RS63955B1 (hr) |
| SG (1) | SG11202003230UA (hr) |
| SI (1) | SI3710586T1 (hr) |
| WO (1) | WO2019092283A1 (hr) |
| ZA (1) | ZA202003371B (hr) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL3389862T3 (pl) | 2015-12-16 | 2024-03-04 | 6K Inc. | Sferoidalne metale podlegające odwodornieniu oraz cząstki stopów metali |
| PL3607069T3 (pl) * | 2017-04-05 | 2023-03-06 | Silence Therapeutics Gmbh | Produkty i kompozycje |
| EP3710588A4 (en) | 2018-01-16 | 2021-08-18 | Dicerna Pharmaceuticals, Inc. | COMPOSITIONS AND METHODS TO INHIBIT ALDH2 EXPRESSION |
| EP3880818B1 (en) * | 2018-11-13 | 2022-09-28 | Silence Therapeutics GmbH | Nucleic acids for inhibiting expression of lpa in a cell |
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| EP3880818B1 (en) | 2018-11-13 | 2022-09-28 | Silence Therapeutics GmbH | Nucleic acids for inhibiting expression of lpa in a cell |
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| DK3710586T3 (da) | 2023-01-23 |
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| KR20200088392A (ko) | 2020-07-22 |
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| AU2018363840A1 (en) | 2020-04-16 |
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| KR102553382B1 (ko) | 2023-07-07 |
| JP2021502120A (ja) | 2021-01-28 |
| FI3710586T3 (fi) | 2023-03-02 |
| US20220290144A1 (en) | 2022-09-15 |
| RS63955B1 (sr) | 2023-02-28 |
| EP3710586B1 (en) | 2022-11-23 |
| US20210123048A1 (en) | 2021-04-29 |
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| IL274503A (en) | 2020-06-30 |
| EP3710586A1 (en) | 2020-09-23 |
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| ZA202003371B (en) | 2023-08-30 |
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| US11319537B2 (en) | 2022-05-03 |
| EP4219716A2 (en) | 2023-08-02 |
| MX2020004897A (es) | 2020-10-05 |
| CN111465694A (zh) | 2020-07-28 |
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