HRP20231606T1 - Spojevi i metode za smanjenje ekspresije tau - Google Patents
Spojevi i metode za smanjenje ekspresije tau Download PDFInfo
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- HRP20231606T1 HRP20231606T1 HRP20231606TT HRP20231606T HRP20231606T1 HR P20231606 T1 HRP20231606 T1 HR P20231606T1 HR P20231606T T HRP20231606T T HR P20231606TT HR P20231606 T HRP20231606 T HR P20231606T HR P20231606 T1 HRP20231606 T1 HR P20231606T1
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- 150000001875 compounds Chemical class 0.000 title claims 17
- 108091034117 Oligonucleotide Proteins 0.000 claims 30
- 150000003839 salts Chemical class 0.000 claims 17
- 239000000825 pharmaceutical preparation Substances 0.000 claims 12
- 230000004770 neurodegeneration Effects 0.000 claims 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims 6
- 201000011240 Frontotemporal dementia Diseases 0.000 claims 5
- 208000024827 Alzheimer disease Diseases 0.000 claims 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims 4
- 239000003085 diluting agent Substances 0.000 claims 4
- 239000002777 nucleoside Substances 0.000 claims 4
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims 4
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical group CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 claims 2
- 208000004051 Chronic Traumatic Encephalopathy Diseases 0.000 claims 2
- 229940104302 cytosine Drugs 0.000 claims 2
- 208000017004 dementia pugilistica Diseases 0.000 claims 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical group P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000002953 phosphate buffered saline Substances 0.000 claims 2
- 125000006850 spacer group Chemical group 0.000 claims 2
- 201000007547 Dravet syndrome Diseases 0.000 claims 1
- 208000024658 Epilepsy syndrome Diseases 0.000 claims 1
- 208000002877 Epileptic Syndromes Diseases 0.000 claims 1
- 208000003098 Ganglion Cysts Diseases 0.000 claims 1
- 208000036572 Myoclonic epilepsy Diseases 0.000 claims 1
- 206010073677 Severe myoclonic epilepsy of infancy Diseases 0.000 claims 1
- 208000005400 Synovial Cyst Diseases 0.000 claims 1
- 208000034799 Tauopathies Diseases 0.000 claims 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims 1
- 230000007850 degeneration Effects 0.000 claims 1
- 206010015037 epilepsy Diseases 0.000 claims 1
- 238000007913 intrathecal administration Methods 0.000 claims 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims 1
- 159000000000 sodium salts Chemical class 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims 1
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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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- A—HUMAN NECESSITIES
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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
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/02—Inorganic compounds
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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
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C12N2310/11—Antisense
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- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/341—Gapmers, i.e. of the type ===---===
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- C12N2310/345—Spatial arrangement of the modifications having at least two different backbone modifications
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- C12N2310/30—Chemical structure
- C12N2310/35—Nature of the modification
- C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
- C12N2310/3525—MOE, methoxyethoxy
Claims (20)
1. Modificirani oligonukleotid prema sljedećoj formuli:
[image]
(SEQ ID NO: 8)
ili njegova sol.
2. Sol modificiranog oligonukleotida prema zahtjevu 1, naznačena time što sol uključuje natrijevu sol i/ili kalijevu sol.
3. Spoj koji sadrži modificirani oligonukleotid, pri čemu je modificirani oligonukleotid gapmer koji se sastoji od segmenta krila od 5', segmenta središnjeg razmaka i segmenta krila od 3', pri čemu:
segment krila 5' sastoji se od pet 2'-MOE nukleozida,
središnji segment praznine sastoji se od osam 2'-deoksinukleozida, i
segment krila 3' sastoji se od pet 2'-MOE nukleozida;
pri čemu modificirani oligonukleotid ima sekvencu nukleobaze 5’- CCGTTTTCTTACCACCCT-3' (SEQ ID NO: 8), pri čemu je svaki citozin 5-metilcitozin; i pri čemu su međumukleozidne veze modificiranog oligonukleotida od 5’ do 3’ sossssssssssssoss, pri čemu je svaki s fosforotioatna veza, a svaki o je fosfodiesterska veza.
4. Spoj koji sadrži modificirani oligonukleotid, pri čemu je modificirani oligonukleotid gapmer koji se sastoji od segmenta krila od 5', segmenta središnjeg razmaka i segmenta krila od 3', pri čemu:
se segment krila 5' sastoji se od pet 2'-MOE nukleozida,
se središnji segment praznine sastoji od osam 2'-deoksinukleozida, i
se segment krila 3' sastoji od pet 2'-MOE nukleozida;
pri čemu modificirani oligonukleotid ima sekvencu nukleobaze 5’- CCGTTTTCTTACCACCCT-3’ (SEQ ID NO: 8), pri čemu je svaki citozin 5-metilcitozin; i pri čemu su međumukleozidne veze modificiranog oligonukleotida od 5’ do 3’ sossssssssssssoss, pri čemu je svaki s fosforotioatna veza, a svaki o je fosfodiesterska veza.
5. Populacija modificiranih oligonukleotida ili njihovih soli prema bilo kojem od zahtjeva 1, 2 ili 4, naznačena time, da su sve fosforotioatne intermukleozidne veze modificiranog oligonukleotida stereoslučajne.
6. Spoj prema zahtjevu 3 ili modificirani oligonukleotid prema zahtjevu 4, naznačen time što je modificirani oligonukleotid vezan na konjugatnu skupinu.
7. Oligomerni dupleks koji sadrži modificirani oligonukleotid ili njegovu sol prema zahtjevu 1 ili 2, spoj prema zahtjevu 3 ili modificirani oligonukleotid prema zahtjevu 4.
8. Farmaceutski pripravak koji sadrži modificirani oligonukleotid ili njegovu sol prema zahtjevu 1 ili 2, spoj prema zahtjevu 3 ili modificirani oligonukleotid prema zahtjevu 4, i farmaceutski prihvatljiv razrjeđivač ili nosač.
9. Farmaceutski pripravak prema zahtjevu 8, naznačen time što sadrži farmaceutski prihvatljiv razrjeđivač, pri čemu je farmaceutski prihvatljiv razrjeđivač fosfatno puferirana fiziološka otopina (PBS) ili umjetni CSF (aCSF).
10. Farmaceutski pripravak prema zahtjevu 9, naznačen time što je farmaceutski prihvatljiv razrjeđivač umjetni CSF (aCSF).
11. Modificirani oligonukleotid ili njegova sol prema zahtjevu 1 ili 2, spoj prema zahtjevu 3, modificirani oligonukleotid prema zahtjevu 4, ili farmaceutski pripravak prema bilo kojem od zahtjeva 8-10, za upotrebu u terapiji.
12. Modificirani oligonukleotid ili njegova sol prema zahtjevu 1 ili 2, spoj prema zahtjevu 3, modificirani oligonukleotid prema zahtjevu 4, ili farmaceutski pripravak prema bilo kojem od zahtjeva 8-10, za upotrebu u liječenju bolesti povezane sa tau.
13. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 12, naznačen time što je bolest povezana s tau neurodegenerativna bolest.
14. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 13, naznačen time što je povezana neurodegenerativna bolest tauopatija.
15. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 13, gdje je neurodegenerativna bolest Alzheimerova bolest, frontotemporalna demencija (FTD), FTDP-17, progresivna supranuklearna paraliza (PSP), kronična traumatska encefalopatija (CTE), Kortikobazalna ganglijska degeneracija (CBD), epilepsija ili Dravetov sindrom.
16. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 15, naznačen time što je neurodegenerativna bolest Alzheimerova bolest.
17. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 16, naznačen time što je Alzheimerova bolest blaga Alzheimerova bolest.
18. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 15, naznačen time što je neurodegenerativna bolest frontotemporalna demencija (FTD).
19. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema zahtjevu 15, naznačen time što je neurodegenerativna bolest progresivna supranuklearna paraliza (PSP).
20. Modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak za upotrebu prema bilo kojem od zahtjeva 11 do 19, naznačen time što se modificirani oligonukleotid, sol, spoj ili farmaceutski pripravak primjenjuje intratekalnom primjenom.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662401723P | 2016-09-29 | 2016-09-29 | |
US201762450469P | 2017-01-25 | 2017-01-25 | |
EP17857565.0A EP3519572B1 (en) | 2016-09-29 | 2017-09-29 | Compounds and methods for reducing tau expression |
PCT/US2017/054540 WO2018064593A1 (en) | 2016-09-29 | 2017-09-29 | Compounds and methods for reducing tau expression |
Publications (1)
Publication Number | Publication Date |
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HRP20231606T1 true HRP20231606T1 (hr) | 2024-03-15 |
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Application Number | Title | Priority Date | Filing Date |
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HRP20231606TT HRP20231606T1 (hr) | 2016-09-29 | 2017-09-29 | Spojevi i metode za smanjenje ekspresije tau |
Country Status (29)
Country | Link |
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US (2) | US10407680B2 (hr) |
EP (2) | EP3519572B1 (hr) |
JP (2) | JP6738004B2 (hr) |
KR (2) | KR20210097228A (hr) |
CN (2) | CN113481201A (hr) |
AU (3) | AU2017336093B2 (hr) |
BR (2) | BR112019003162B1 (hr) |
CA (1) | CA3038891A1 (hr) |
CL (2) | CL2019000703A1 (hr) |
CO (1) | CO2019001385A2 (hr) |
CR (2) | CR20190214A (hr) |
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