JP2020529197A5 - - Google Patents

Info

Publication number

JP2020529197A5

JP2020529197A5 JP2019572382A JP2019572382A JP2020529197A5 JP 2020529197 A5 JP2020529197 A5 JP 2020529197A5 JP 2019572382 A JP2019572382 A JP 2019572382A JP 2019572382 A JP2019572382 A JP 2019572382A JP 2020529197 A5 JP2020529197 A5 JP 2020529197A5

Authority

JP

Japan

Prior art keywords

seq

oligonucleotide

nucleotides

antisense strand

sense strand

Prior art date

2018-06-29

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Pending

Links

• Espacenet
• Global Dossier
• Discuss

• 108091034117 Oligonucleotide Proteins 0.000 claims description 113
• 125000003729 nucleotide group Chemical group 0.000 claims description 67
• 239000002773 nucleotide Substances 0.000 claims description 58
• 230000000692 anti-sense effect Effects 0.000 claims description 53
• 108091081021 Sense strand Proteins 0.000 claims description 48
• 102000055207 HMGB1 Human genes 0.000 claims description 23
• 108700010013 HMGB1 Proteins 0.000 claims description 23
• 230000000295 complement effect Effects 0.000 claims description 23
• 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 claims description 22
• 101150021904 HMGB1 gene Proteins 0.000 claims description 22
• 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 description 13
• 239000003446 ligand Substances 0.000 claims description 11
• 238000012986 modification Methods 0.000 claims description 9
• 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 6
• 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 6
• 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 6
• 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 Polymers 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 description 5
• 229910052799 carbon Inorganic materials 0.000 claims description 4
• 239000000203 mixture Substances 0.000 claims description 4
• 230000004048 modification Effects 0.000 claims description 4
• 206010008635 Cholestasis Diseases 0.000 claims description 3
• 208000027761 Hepatic autoimmune disease Diseases 0.000 claims description 3
• 239000002253 acid Substances 0.000 claims description 3
• 231100000359 cholestasis Toxicity 0.000 claims description 3
• 230000007870 cholestasis Effects 0.000 claims description 3
• 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
• ZTWTYVWXUKTLCP-UHFFFAOYSA-L ethenyl-dioxido-oxo-$l^{5}-phosphane Chemical compound [O-]P([O-])(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-L 0.000 claims description 3
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 3
• 108020004999 messenger RNA Proteins 0.000 claims description 2
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 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
• 230000008685 targeting Effects 0.000 claims 2
• MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 claims 1
• CTVFZKJXQWDXIO-UHFFFAOYSA-N P1(OC(CC(=O)O1)=O)=O Chemical compound P1(OC(CC(=O)O1)=O)=O CTVFZKJXQWDXIO-UHFFFAOYSA-N 0.000 claims 1
• MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 claims 1
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims 1
• 208000024891 symptom Diseases 0.000 claims 1
• 238000000034 method Methods 0.000 description 14
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
• 239000003795 chemical substances by application Substances 0.000 description 3
• 231100000334 hepatotoxic Toxicity 0.000 description 3
• 230000003082 hepatotoxic effect Effects 0.000 description 3
• 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 description 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 description 2
• 150000007513 acids Chemical class 0.000 description 2
• 150000001720 carbohydrates Chemical class 0.000 description 2
• 235000014633 carbohydrates Nutrition 0.000 description 2
• 235000012000 cholesterol Nutrition 0.000 description 2
• 150000002337 glycosamines Chemical class 0.000 description 2
• 150000002632 lipids Chemical class 0.000 description 2
• 229920001184 polypeptide Polymers 0.000 description 2
• 102000004196 processed proteins & peptides Human genes 0.000 description 2
• 108090000765 processed proteins & peptides Proteins 0.000 description 2
• 108091023037 Aptamer Proteins 0.000 description 1
• 108091030071 RNAI Proteins 0.000 description 1
• 230000009368 gene silencing by RNA Effects 0.000 description 1
• 230000002440 hepatic effect Effects 0.000 description 1
• 230000035772 mutation Effects 0.000 description 1
• 210000002966 serum Anatomy 0.000 description 1