JP6830441B2 - 治療上のunaオリゴマーおよびその使用 - Google Patents
治療上のunaオリゴマーおよびその使用 Download PDFInfo
- Publication number
- JP6830441B2 JP6830441B2 JP2017551098A JP2017551098A JP6830441B2 JP 6830441 B2 JP6830441 B2 JP 6830441B2 JP 2017551098 A JP2017551098 A JP 2017551098A JP 2017551098 A JP2017551098 A JP 2017551098A JP 6830441 B2 JP6830441 B2 JP 6830441B2
- Authority
- JP
- Japan
- Prior art keywords
- una
- oligomer
- monomer
- monomers
- oligomers
- Prior art date
- 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.)
- Active
Links
- 230000001225 therapeutic effect Effects 0.000 title claims description 4
- 239000000178 monomer Substances 0.000 claims description 291
- 125000003729 nucleotide group Chemical class 0.000 claims description 62
- 239000002773 nucleotide Substances 0.000 claims description 45
- 230000014509 gene expression Effects 0.000 claims description 30
- 230000000694 effects Effects 0.000 claims description 27
- 238000001727 in vivo Methods 0.000 claims description 24
- 238000000338 in vitro Methods 0.000 claims description 23
- 108020004707 nucleic acids Proteins 0.000 claims description 22
- 102000039446 nucleic acids Human genes 0.000 claims description 22
- 150000007523 nucleic acids Chemical class 0.000 claims description 21
- 230000005923 long-lasting effect Effects 0.000 claims description 19
- 108090000623 proteins and genes Proteins 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 11
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 claims description 10
- 230000009368 gene silencing by RNA Effects 0.000 claims description 10
- 206010002022 amyloidosis Diseases 0.000 claims description 7
- 108020004999 messenger RNA Proteins 0.000 claims description 7
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 108010071690 Prealbumin Proteins 0.000 claims description 4
- 102000009190 Transthyretin Human genes 0.000 claims description 4
- 208000003808 Amyloid Neuropathies Diseases 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000005414 inactive ingredient Substances 0.000 claims description 3
- 238000007385 chemical modification Methods 0.000 claims description 2
- 206010059047 Amyloidoma Diseases 0.000 claims 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 claims 1
- 230000002222 downregulating effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 54
- 230000008685 targeting Effects 0.000 description 39
- 238000000034 method Methods 0.000 description 22
- 241000700721 Hepatitis B virus Species 0.000 description 16
- 230000000692 anti-sense effect Effects 0.000 description 16
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 15
- 102100030970 Apolipoprotein C-III Human genes 0.000 description 15
- 101001098868 Homo sapiens Proprotein convertase subtilisin/kexin type 9 Proteins 0.000 description 15
- 102100038955 Proprotein convertase subtilisin/kexin type 9 Human genes 0.000 description 15
- 239000003795 chemical substances by application Substances 0.000 description 15
- 101000889953 Homo sapiens Apolipoprotein B-100 Proteins 0.000 description 14
- 101000793223 Homo sapiens Apolipoprotein C-III Proteins 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 230000002401 inhibitory effect Effects 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 10
- -1 propane-1,2,3-tri-yl-trisoxy structure Chemical group 0.000 description 10
- 239000013543 active substance Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 231100000673 dose–response relationship Toxicity 0.000 description 8
- 230000030279 gene silencing Effects 0.000 description 8
- 238000012226 gene silencing method Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 108060001084 Luciferase Proteins 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 235000012000 cholesterol Nutrition 0.000 description 5
- 239000005089 Luciferase Substances 0.000 description 4
- 241000242743 Renilla reniformis Species 0.000 description 4
- 108020004459 Small interfering RNA Proteins 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 238000001890 transfection Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 3
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 3
- 108700005077 Viral Genes Proteins 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 108020005345 3' Untranslated Regions Proteins 0.000 description 2
- 101150102415 Apob gene Proteins 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- 101150094724 PCSK9 gene Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000013614 RNA sample Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101150091380 TTR gene Proteins 0.000 description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000001819 effect on gene Effects 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 208000006575 hypertriglyceridemia Diseases 0.000 description 2
- 230000028709 inflammatory response Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 2
- 230000009437 off-target effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920000768 polyamine Polymers 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
- 239000003998 snake venom Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 1
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 1
- TYNSUEXNGLNQSS-UHFFFAOYSA-N 6-carbamoyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(N)=O TYNSUEXNGLNQSS-UHFFFAOYSA-N 0.000 description 1
- ASUCSHXLTWZYBA-UMMCILCDSA-N 8-Bromoguanosine Chemical compound C1=2NC(N)=NC(=O)C=2N=C(Br)N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ASUCSHXLTWZYBA-UMMCILCDSA-N 0.000 description 1
- 101150001527 APOC3 gene Proteins 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 101710095342 Apolipoprotein B Proteins 0.000 description 1
- 108010056301 Apolipoprotein C-III Proteins 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010054576 Deoxyribonuclease EcoRI Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 108090000331 Firefly luciferases Proteins 0.000 description 1
- 241000125974 Galene <Rhodophyta> Species 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 101710172072 Kexin Proteins 0.000 description 1
- 241000254158 Lampyridae Species 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- VQAYFKKCNSOZKM-IOSLPCCCSA-N N(6)-methyladenosine Chemical class C1=NC=2C(NC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VQAYFKKCNSOZKM-IOSLPCCCSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 238000009004 PCR Kit Methods 0.000 description 1
- 108010010677 Phosphodiesterase I Proteins 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical group CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 108090000787 Subtilisin Proteins 0.000 description 1
- 241000884498 Thatuna Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 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 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 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229940124447 delivery agent Drugs 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010864 dual luciferase reporter gene assay Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 230000037440 gene silencing effect Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 229940060367 inert ingredients Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000003509 long acting drug Substances 0.000 description 1
- 238000003468 luciferase reporter gene assay Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 108091070501 miRNA Proteins 0.000 description 1
- 239000002679 microRNA Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 125000000548 ribosyl group Chemical class C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- 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
- C12N15/1131—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 viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
-
- A—HUMAN NECESSITIES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/31—Chemical structure of the backbone
- C12N2310/315—Phosphorothioates
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/321—2'-O-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/322—2'-R Modification
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/32—Chemical structure of the sugar
- C12N2310/323—Chemical structure of the sugar modified ring structure
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/34—Spatial arrangement of the modifications
- C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/51—Methods for regulating/modulating their activity modulating the chemical stability, e.g. nuclease-resistance
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/50—Methods for regulating/modulating their activity
- C12N2320/52—Methods for regulating/modulating their activity modulating the physical stability, e.g. GC-content
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Zoology (AREA)
- Wood Science & Technology (AREA)
- General Engineering & Computer Science (AREA)
- Virology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Microbiology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
配列表
UNA−A(
と命名する)、UNA−U(
と命名する)、UNA−C(
と命名する)、およびUNA−G(
と命名する)となることができる。
Claims (18)
- 第1鎖および第2鎖を含むUNAオリゴマーであって、各々の鎖は19〜29モノマー長であり、該モノマーはUNAモノマーおよび核酸モノマーを含み、ここに該オリゴマーは14〜29モノマー長の二本鎖構造を有し、ここに該第2鎖はRNA干渉用のガイド鎖であって該第1鎖はRNA干渉用のパッセンジャー鎖であり、ここに
(a)第1鎖は配列番号:239であり、第2鎖は配列番号:240である、または
(b)第1鎖は配列番号:263であり、第2鎖は配列番号:264である、
およびここにUNAオリゴマーはターゲット遺伝子の発現を低下させる、UNAオリゴマー。 - 各々の鎖に1またはそれを超える核酸モノマーの1またはそれを超える化学修飾を含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが2'−O−メチル基で修飾された1またはそれを超えるヌクレオチドを含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが2'−O−メチル基で修飾された1〜9のヌクレオチドを含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが2'−デオキシ−2'−フルオロ基で修飾された1またはそれを超えるヌクレオチドを含む、請求項1に記載のUNAオリゴマー。
- いずれかの鎖における1またはそれを超えるモノマー間結合がホスホロチオエートまたはキラルホスホロチオエート結合である、請求項1に記載のUNAオリゴマー。
- オリゴマーが2'−O−メチル基で修飾された1またはそれを超えるヌクレオチドおよび2'−デオキシ−2'−フルオロ基で修飾された1またはそれを超えるヌクレオチドを含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが、いずれかの鎖に2'−O−メチル基で修飾された1またはそれを超えるヌクレオチド、2'−デオキシ−2'−フルオロ基で修飾された1またはそれを超えるヌクレオチド、および1またはそれを超えるホスホロチオエートまたはキラルホスホロチオエートモノマー間結合を含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが、いずれかの鎖に3またはそれを超えるUNAモノマー、2'−O−メチル基で修飾された1またはそれを超えるヌクレオチド、2'−デオキシ−2'−フルオロ基で修飾された1またはそれを超えるヌクレオチド、および1またはそれを超えるホスホロチオエートまたはキラルホスホロチオエートモノマー間結合を含む、請求項1に記載のUNAオリゴマー。
- オリゴマーが(a)または(b)から選択され、ターゲット遺伝子がTTRである、請求項1に記載のUNAオリゴマー。
- UNAオリゴマーがイン・ビトロ(in vitro)において長時間持続する活性を有する、請求項1に記載のUNAオリゴマー。
- UNAオリゴマーがイン・ビボ(in vivo)において長時間持続する効能を有する、請求項1に記載のUNAオリゴマー。
- 請求項1〜12のいずれかに記載の1またはそれを超えるUNAオリゴマーおよび医薬上許容し得る不活性成分、希釈剤または補助剤を含む医薬組成物。
- ターゲット遺伝子の発現を下方調節するための薬物の調製における請求項1〜12のいずれかに記載の1またはそれを超えるUNAオリゴマーまたは請求項13記載の医薬組成物の使用。
- 必要とする対象において、アミロイド神経障害またはアミロイドーシスを予防または治療するための薬物の調製における、請求項13記載の医薬組成物の使用。
- 治療ターゲット用の薬物の調製における、請求項13記載の組成物の使用。
- 細胞中のターゲットmRNAの発現レベルを低下させる薬物を調製することにおける、請求項1〜12のいずれかに記載の1またはそれを超えるUNAオリゴマーの使用。
- アミロイドーシスがトランスサイレチンに関連するアミロイドーシスである、請求項15記載の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562141261P | 2015-04-01 | 2015-04-01 | |
US62/141,261 | 2015-04-01 | ||
PCT/US2016/025578 WO2016161299A1 (en) | 2015-04-01 | 2016-04-01 | Therapeutic una oligomers and uses thereof |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018512140A JP2018512140A (ja) | 2018-05-17 |
JP2018512140A5 JP2018512140A5 (ja) | 2019-03-28 |
JP6830441B2 true JP6830441B2 (ja) | 2021-02-17 |
Family
ID=57004616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017551098A Active JP6830441B2 (ja) | 2015-04-01 | 2016-04-01 | 治療上のunaオリゴマーおよびその使用 |
Country Status (4)
Country | Link |
---|---|
US (1) | US10519447B2 (ja) |
EP (1) | EP3277289A4 (ja) |
JP (1) | JP6830441B2 (ja) |
WO (1) | WO2016161299A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20240309366A1 (en) * | 2020-12-31 | 2024-09-19 | Arcturus Therapeutics, Inc. | Compositions and methods for treating metabolic disorders |
Family Cites Families (67)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4199574A (en) | 1974-09-02 | 1980-04-22 | Burroughs Wellcome Co. | Methods and compositions for treating viral infections and guanine acyclic nucleosides |
US4968686A (en) | 1988-04-08 | 1990-11-06 | The Regents Of The University Of Michigan | Acyclic pyrrolo [2,3-d]pyrimidine analogs as antiviral agents |
US5786359A (en) | 1994-05-27 | 1998-07-28 | The Scripps Research Institute | N9 alkyl or aralkyl derivatives of 7, 8-disubstituted guanines |
US6608035B1 (en) | 1994-10-25 | 2003-08-19 | Hybridon, Inc. | Method of down-regulating gene expression |
GB9505025D0 (en) | 1995-03-13 | 1995-05-03 | Medical Res Council | Chemical compounds |
WO2005121370A2 (en) | 2004-06-03 | 2005-12-22 | Isis Pharmaceuticals, Inc. | Oligomeric compounds that facilitate risc loading |
US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US6069132A (en) | 1996-08-14 | 2000-05-30 | Revanker; Ganapathi R. | Phosphazole compounds |
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
US6037176A (en) | 1999-06-25 | 2000-03-14 | Isis Pharmaceuticals Inc. | Antisense inhibition of integrin beta 3 expression |
GB9925459D0 (en) | 1999-10-27 | 1999-12-29 | Plant Bioscience Ltd | Gene silencing |
US7829693B2 (en) | 1999-11-24 | 2010-11-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
WO2002081628A2 (en) | 2001-04-05 | 2002-10-17 | Ribozyme Pharmaceuticals, Incorporated | Modulation of gene expression associated with inflammation proliferation and neurite outgrowth, using nucleic acid based technologies |
US8202979B2 (en) | 2002-02-20 | 2012-06-19 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid |
WO2003070918A2 (en) | 2002-02-20 | 2003-08-28 | Ribozyme Pharmaceuticals, Incorporated | Rna interference by modified short interfering nucleic acid |
AU2001249622B2 (en) | 2000-03-30 | 2007-06-07 | Massachusetts Institute Of Technology | RNA sequence-specific mediators of RNA interference |
WO2002044321A2 (en) | 2000-12-01 | 2002-06-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Rna interference mediating small rna molecules |
US8546143B2 (en) | 2001-01-09 | 2013-10-01 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
WO2007022369A2 (en) | 2005-08-17 | 2007-02-22 | Sirna Therapeutics, Inc. | Chemically modified short interfering nucleic acid molecules that mediate rna interference |
JP2005504020A (ja) | 2001-07-03 | 2005-02-10 | アイシス・ファーマシューティカルス・インコーポレーテッド | ヌクレアーゼ耐性キメラオリゴヌクレオチド |
WO2003006477A1 (en) | 2001-07-12 | 2003-01-23 | University Of Massachusetts | IN VIVO PRODUCTION OF SMALL INTERFERING RNAs THAT MEDIATE GENE SILENCING |
WO2003037909A1 (en) | 2001-10-29 | 2003-05-08 | Mcgill University | Acyclic linker-containing oligonucleotides and uses thereof |
US7388002B2 (en) | 2001-11-14 | 2008-06-17 | Biocryst Pharmaceuticals, Inc. | Nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases |
US7897753B2 (en) | 2002-02-20 | 2011-03-01 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of XIAP gene expression using short interfering nucleic acid (siNA) |
AU2003248708A1 (en) | 2002-06-17 | 2003-12-31 | Isis Pharmaceuticals, Inc. | Oligomeric compounds that include carbocyclic nucleosides and their use in gene modulation |
US7956176B2 (en) | 2002-09-05 | 2011-06-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
AU2003291753B2 (en) | 2002-11-05 | 2010-07-08 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
US20040261149A1 (en) | 2003-02-24 | 2004-12-23 | Fauquet Claude M. | siRNA-mediated inhibition of gene expression in plant cells |
CA2518475C (en) | 2003-03-07 | 2014-12-23 | Alnylam Pharmaceuticals, Inc. | Irna agents comprising asymmetrical modifications |
WO2004090105A2 (en) | 2003-04-02 | 2004-10-21 | Dharmacon, Inc. | Modified polynucleotides for use in rna interference |
AU2004227414A1 (en) | 2003-04-03 | 2004-10-21 | Alnylam Pharmaceuticals | iRNA conjugates |
JP4597976B2 (ja) | 2003-04-17 | 2010-12-15 | アルナイラム ファーマシューティカルズ インコーポレイテッド | 修飾iRNA剤 |
EP3502252B1 (en) | 2003-06-02 | 2023-04-05 | University of Massachusetts | Methods and compositions for controlling efficacy of rna silencing |
US7750144B2 (en) | 2003-06-02 | 2010-07-06 | University Of Massachusetts | Methods and compositions for enhancing the efficacy and specificity of RNA silencing |
WO2004108897A2 (en) | 2003-06-02 | 2004-12-16 | Cytokinetics, Inc. | Sirna libraries |
AU2004263830B2 (en) | 2003-06-13 | 2008-12-18 | Alnylam Pharmaceuticals, Inc. | Double-stranded ribonucleic acid with increased effectiveness in an organism |
AU2004263130A1 (en) | 2003-08-06 | 2005-02-17 | Nirmal Mulye | Pharmaceutical composition containing water soluble drug |
US8790919B2 (en) | 2004-03-15 | 2014-07-29 | Isis Pharmaceuticals, Inc. | Compositions and methods for optimizing cleavage of RNA by RNase H |
AU2005222965B8 (en) | 2004-03-15 | 2010-07-01 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
KR101147147B1 (ko) | 2004-04-01 | 2012-05-25 | 머크 샤프 앤드 돔 코포레이션 | Rna 간섭의 오프 타겟 효과 감소를 위한 변형된폴리뉴클레오타이드 |
EP1750776A2 (en) | 2004-04-30 | 2007-02-14 | Alnylam Pharmaceuticals Inc. | Oligonucleotides comprising a c5-modified pyrimidine |
JP2008504840A (ja) | 2004-06-30 | 2008-02-21 | アルニラム ファーマスーティカルズ インコーポレイテッド | 非リン酸骨格結合を含むオリゴヌクレオチド |
US7297786B2 (en) | 2004-07-09 | 2007-11-20 | University Of Iowa Research Foundation | RNA interference in respiratory epitheial cells |
US7579451B2 (en) | 2004-07-21 | 2009-08-25 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a modified or non-natural nucleobase |
CA2574603C (en) | 2004-08-04 | 2014-11-04 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase |
WO2007051303A1 (en) | 2005-11-02 | 2007-05-10 | Protiva Biotherapeutics, Inc. | MODIFIED siRNA MOLECULES AND USES THEREOF |
JP5078904B2 (ja) | 2005-11-21 | 2012-11-21 | ジヨンソン・アンド・ジヨンソン・リサーチ・ピーテイワイ・リミテツド | 多標的干渉rnaならびにそれらの使用および設計方法 |
US7915399B2 (en) | 2006-06-09 | 2011-03-29 | Protiva Biotherapeutics, Inc. | Modified siRNA molecules and uses thereof |
WO2008020435A2 (en) | 2006-08-15 | 2008-02-21 | Quark Pharmaceuticals, Inc | Compositions and methods for treatment of mood disorders |
EP2162538B1 (en) * | 2007-05-22 | 2016-04-20 | Arcturus Therapeutics, Inc. | Oligomers for therapeutics |
EP2315831A2 (en) | 2008-08-05 | 2011-05-04 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting plk1 gene expression and uses thereof |
CN103937793B (zh) | 2008-10-20 | 2017-08-11 | 阿尔尼拉姆医药品有限公司 | 抑制运甲状腺素蛋白表达的组合物和方法 |
CN104673798B (zh) * | 2008-12-03 | 2018-03-20 | 阿克丘勒斯治疗公司 | UsiRNA复合物 |
CA2792291A1 (en) | 2010-03-29 | 2011-10-06 | Kumamoto University | Sirna therapy for transthyretin (ttr) related ocular amyloidosis |
WO2011133584A2 (en) | 2010-04-19 | 2011-10-27 | Marina Biotech, Inc. | Nucleic acid compounds for inhibiting hras gene expression and uses thereof |
US20130190383A1 (en) | 2010-04-26 | 2013-07-25 | Marina Biotech, Inc. | Nucleic acid compounds with conformationally restricted monomers and uses thereof |
WO2012068413A1 (en) | 2010-11-17 | 2012-05-24 | Huawei Technologies Co., Ltd. | Methods and apparatus for inter-cell interference coordination self-organized network |
WO2012177906A1 (en) * | 2011-06-21 | 2012-12-27 | Alnylam Pharmaceuticals, Inc. | Assays and methods for determining activity of a therapeutic agent in a subject |
DK3301177T3 (da) | 2011-11-18 | 2020-06-15 | Alnylam Pharmaceuticals Inc | Rnai-midler, sammensætninger og fremgangsmåder til anvendelse deraf til behandling af transthyretin (ttr)-forbundne sygdomme |
GR1008018B (el) | 2012-09-06 | 2013-10-29 | Ιδρυμα Ιατροβιολογικων Ερευνων Ακαδημιας Αθηνων, | Λιπιδικα συμπλοκα αποτελουμενα απο ανιονικα λυσο-λιπιδια και η εφαρμογη αυτων |
WO2015042564A1 (en) * | 2013-09-23 | 2015-03-26 | Alnylam Pharmaceuticals, Inc. | Methods for treating or preventing transthyretin (ttr) associated diseases |
US9365610B2 (en) | 2013-11-18 | 2016-06-14 | Arcturus Therapeutics, Inc. | Asymmetric ionizable cationic lipid for RNA delivery |
US9593077B2 (en) | 2013-11-18 | 2017-03-14 | Arcturus Therapeutics, Inc. | Ionizable cationic lipid for RNA delivery |
US9856475B2 (en) * | 2014-03-25 | 2018-01-02 | Arcturus Therapeutics, Inc. | Formulations for treating amyloidosis |
JP6771387B2 (ja) | 2014-03-25 | 2020-10-21 | アークトゥラス・セラピューティクス・インコーポレイテッドArcturus Therapeutics,Inc. | 遺伝子サイレンシング用トランスサイレチン対立遺伝子選択的unaオリゴマー |
AU2015236215B2 (en) * | 2014-03-25 | 2020-03-19 | Arcturus Therapeutics, Inc. | UNA oligomers having reduced off-target effects in gene silencing |
-
2016
- 2016-04-01 US US15/563,579 patent/US10519447B2/en active Active
- 2016-04-01 EP EP16774322.8A patent/EP3277289A4/en active Pending
- 2016-04-01 WO PCT/US2016/025578 patent/WO2016161299A1/en unknown
- 2016-04-01 JP JP2017551098A patent/JP6830441B2/ja active Active
Also Published As
Publication number | Publication date |
---|---|
US10519447B2 (en) | 2019-12-31 |
EP3277289A4 (en) | 2018-12-05 |
JP2018512140A (ja) | 2018-05-17 |
WO2016161299A1 (en) | 2016-10-06 |
US20180105816A1 (en) | 2018-04-19 |
EP3277289A1 (en) | 2018-02-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7442574B2 (ja) | Lpaの遺伝子発現の阻害のための組成物及び方法 | |
JP6752151B2 (ja) | 遺伝子サイレンシングにおいて低下したoff−target効果を有するunaオリゴマー | |
JP6924744B2 (ja) | B型肝炎ウイルスに対する組成物および薬剤ならびにその使用 | |
JP7049262B2 (ja) | 結合組織成長因子を標的とするrna複合体を用いた特発性肺胞線維症の治療 | |
KR20190042660A (ko) | 화학적으로 변형된 단일 가닥 rna-편집 올리고뉴클레오타이드 | |
WO2008109452B1 (en) | Nucleic acid compounds for inhibiting tie gene expression and uses thereof | |
JP2005533517A (ja) | 修飾された低分子干渉rna分子および使用方法 | |
BR112020020220A2 (pt) | Uso de inibidores da fubp1 para o tratamento de infecção pelo vírus da hepatite b | |
JP2009513112A (ja) | アラビノース修飾ヌクレオチドを含む低分子干渉リボ核酸二重鎖 | |
TW202020152A (zh) | 調節rtel1表現之寡核苷酸 | |
JP6830441B2 (ja) | 治療上のunaオリゴマーおよびその使用 | |
WO2022248879A1 (en) | Composition and method for adar-mediated rna editing | |
JP2023506546A (ja) | B型肝炎ウイルス感染症を処置するためのsept9阻害剤の使用 | |
JP2023538630A (ja) | B型肝炎ウイルス感染症を処置するためのa1cf阻害剤の使用 | |
JP2023506540A (ja) | B型肝炎ウイルス感染を処置するためのscamp3阻害剤の使用 | |
JP2023506954A (ja) | B型肝炎ウイルス感染を処置するためのsaraf阻害剤の使用 | |
JP2023506547A (ja) | B型肝炎ウイルス感染を処置するためのcops3阻害剤の使用 | |
KR20240110595A (ko) | 안정화된 rna 제제 | |
CN114829601A (zh) | Sbds抑制剂用于治疗乙型肝炎病毒感染的用途 | |
WO2017027814A1 (en) | Una oligomeric agents for stimulating cystic fibrosis transmembrane conductance regulator and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190215 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190215 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20191108 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191210 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200309 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200602 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200930 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20200930 |
|
C11 | Written invitation by the commissioner to file amendments |
Free format text: JAPANESE INTERMEDIATE CODE: C11 Effective date: 20201013 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20201201 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20201208 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20210112 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210126 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6830441 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |