JPH06500087A - 新規のポリアミン結合オリゴヌクレオチド - Google Patents
新規のポリアミン結合オリゴヌクレオチドInfo
- Publication number
- JPH06500087A JPH06500087A JP3513696A JP51369691A JPH06500087A JP H06500087 A JPH06500087 A JP H06500087A JP 3513696 A JP3513696 A JP 3513696A JP 51369691 A JP51369691 A JP 51369691A JP H06500087 A JPH06500087 A JP H06500087A
- Authority
- JP
- Japan
- Prior art keywords
- oligonucleotide
- nucleoside
- polyamine
- functional group
- nnh
- 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.)
- Pending
Links
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 108
- 229920000768 polyamine Polymers 0.000 title claims abstract description 61
- 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 title claims abstract description 39
- 238000000034 method Methods 0.000 claims description 58
- 239000002777 nucleoside Substances 0.000 claims description 50
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 36
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 33
- 125000000524 functional group Chemical group 0.000 claims description 17
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 16
- 229940104230 thymidine Drugs 0.000 claims description 15
- 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 claims description 14
- 230000000692 anti-sense effect Effects 0.000 claims description 14
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 14
- 125000003729 nucleotide group Chemical group 0.000 claims description 14
- 125000003835 nucleoside group Chemical group 0.000 claims description 13
- 239000002773 nucleotide Substances 0.000 claims description 13
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 11
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 10
- 238000012230 antisense oligonucleotides Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 8
- BRWIZMBXBAOCCF-UHFFFAOYSA-N thiosemicarbazide group Chemical group NNC(=S)N BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 4
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 208000003154 papilloma Diseases 0.000 claims description 3
- 230000014616 translation Effects 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 238000010348 incorporation Methods 0.000 claims description 2
- XEVRDFDBXJMZFG-UHFFFAOYSA-N carbonyl dihydrazine Chemical group NNC(=O)NN XEVRDFDBXJMZFG-UHFFFAOYSA-N 0.000 claims 3
- 230000001105 regulatory effect Effects 0.000 claims 1
- 230000004048 modification Effects 0.000 abstract description 11
- 238000012986 modification Methods 0.000 abstract description 11
- 101710163270 Nuclease Proteins 0.000 abstract description 9
- 230000004700 cellular uptake Effects 0.000 abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 6
- 150000002429 hydrazines Chemical class 0.000 abstract 1
- 150000001412 amines Chemical class 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- -1 alkyl triester Chemical class 0.000 description 12
- 239000002585 base Substances 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 8
- 239000005289 controlled pore glass Substances 0.000 description 7
- 150000008300 phosphoramidites Chemical class 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 6
- 108020004414 DNA Proteins 0.000 description 6
- 101710149951 Protein Tat Proteins 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 150000003141 primary amines Chemical class 0.000 description 5
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 5
- VOWRYWPKXSMTOK-UHFFFAOYSA-N (amino-tert-butyl-phenylsilyl)benzene Chemical compound C=1C=CC=CC=1[Si](N)(C(C)(C)C)C1=CC=CC=C1 VOWRYWPKXSMTOK-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000295 complement effect Effects 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- BKHGFBHADSLTHZ-UHFFFAOYSA-N n',n'-bis(4-aminobutyl)butane-1,4-diamine Chemical compound NCCCCN(CCCCN)CCCCN BKHGFBHADSLTHZ-UHFFFAOYSA-N 0.000 description 4
- 229910052698 phosphorus Inorganic materials 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 241001529453 unidentified herpesvirus Species 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241001631646 Papillomaviridae Species 0.000 description 3
- 239000004952 Polyamide Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group 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 3
- 229960005215 dichloroacetic acid Drugs 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 238000005731 phosphitylation reaction Methods 0.000 description 3
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 3
- 229920002647 polyamide Polymers 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VNOPDYRWCWFIBS-KBVBSXBZSA-N 1-[(2r,4s,5r)-4-acetyl-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O1[C@H](CO)[C@@](C(=O)C)(O)C[C@@H]1N1C(=O)NC(=O)C(C)=C1 VNOPDYRWCWFIBS-KBVBSXBZSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100459439 Caenorhabditis elegans nac-2 gene Proteins 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
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- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
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- 230000002829 reductive effect Effects 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 235000001508 sulfur Nutrition 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
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- SWGZHHCRMZDRSN-BTJKTKAUSA-N (Z)-but-2-enedioic acid 1-phenoxypropan-2-ylhydrazine Chemical compound OC(=O)\C=C/C(O)=O.NNC(C)COC1=CC=CC=C1 SWGZHHCRMZDRSN-BTJKTKAUSA-N 0.000 description 1
- AZINJOAUEDYASP-UHFFFAOYSA-N 1-n,1-n'-diphenylethane-1,1-diamine Chemical compound C=1C=CC=CC=1NC(C)NC1=CC=CC=C1 AZINJOAUEDYASP-UHFFFAOYSA-N 0.000 description 1
- MKSUIIJJRMJEEW-UHFFFAOYSA-N 3-amino-6-[bis(4-aminobutyl)amino]-1,1,1,8,8,8-hexafluoro-3-(2,2,2-trifluoroacetyl)octane-2,7-dione Chemical compound NCCCCN(CCCCN)C(C(=O)C(F)(F)F)CCC(N)(C(=O)C(F)(F)F)C(=O)C(F)(F)F MKSUIIJJRMJEEW-UHFFFAOYSA-N 0.000 description 1
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- NOUUUQMKVOUUNR-UHFFFAOYSA-N n,n'-diphenylethane-1,2-diamine Chemical compound C=1C=CC=CC=1NCCNC1=CC=CC=C1 NOUUUQMKVOUUNR-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
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- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000007659 semicarbazones Chemical class 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000002345 steroid group Chemical group 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 1
- 235000019157 thiamine Nutrition 0.000 description 1
- 229960003495 thiamine Drugs 0.000 description 1
- 239000011721 thiamine Substances 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 238000005583 trifluoroacetylation reaction Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
Classifications
-
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
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Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。
Description
【発明の詳細な説明】
新規のポリアミン結合オリゴヌクレオチド発明の分野
本発明は、治療法の分野に関し、特に、アンチセンス療法による感染の治療に関
する0本発明は、更に、遺伝子発現の分野に関する。アンチセンス療法において
有用である新規のポリアミン結合ホスホロチオエートオリゴヌクレオチドを提供
する。これらのオリゴヌクレオチドは細胞の取込みを増大させ、そしてその結果
として生物学的および治療学的活性を増大させた。更に、本発明は、新規のポリ
アミン結合ホスホロチオエートオリゴヌクレオチドの合成法を提供する。
発明の背景
大部分の疾患状態を含む哺乳動物における大部分の身体的状態かタンパク質によ
って影響されていることは周知である。直接的にまたはそれらの酵素機能を介し
て作用するこのようなタンパク質は、主要な割合で動物およびヒトにおける多く
の疾患の一因となっている。古典的治療法は、概して、このようなタンパク質の
疾患を引き起こす機能または疾患を強力にする機能を調節するための研究におい
て該タンパク質との相互作用に関心か向けられてきた。しかしながら、近年、こ
のようなタンパク質の実際の産生を、それらの合成を支配する分子である細胞内
RNAとの相互作用によって調節する試みがなされた。これらの相互作用は、相
補的「アンチセンス」オリゴヌクレオチドまたはそれらの類似体かワトソン・ク
リック塩基対相互作用によるような配列特異的様式で細胞内RNAに対して結合
することを必要とした。
アンチセンスオリゴヌクレオチドの薬理学的活性並びに他の治療法は、特定の細
胞内標的でのこれらの物質の有効濃度に影響を及ぼす多数の因子に依存する。
一つの重要な因子はヌクレアーゼ存在下におけるオリゴヌクレオチドの安定性で
ある。もう一つの重要な因子は、疾患経過に関係した特定の細胞の原形質膜を通
過するアンチセンス化合物の能力である。
細胞膜は、小さい非イオン性の親油性化合物に対して自由に透過性であり且つ大
部分の天然代謝生成物および治療薬に対して本来的に透過性である脂質タンパク
質二重層から成る、ウィルソン(Wi I 5on)、D、B、、Ann、Re
vBiochem、47 : 933〜965 (1978)、培養された哺乳
動物細胞における天然のおよび修飾されたオリゴヌクレオチドの生物学的および
抗ウイルス性作用は十分に実証されており、これらの物質は膜に浸透してそれら
の細胞内標的に到達することかできると考えられる。HL−60、シリアンハム
スター(Syrian Hamste’r)″m維芽細胞、U937、L929
、CV−1およびATH8細胞を含む種々の哺乳動物細胞中へのアンチセンス化
合物の取込みは、天然オリゴヌクレオチドおよびヌクレアーゼ耐性類似体、例え
ば、アルキルトリエステル[ミラー(Mi l 1er)、P、S、、ブライタ
マン(Braiterman)、L、T、およびTs′O,P、O,P、。
Biochemistry 工6 :1988〜1996 (1977)コ;メ
チルホスホネート[マークス・セクラ<Marcus−3ekura)、C,H
,。
ワーナー(Woerner)、A、M、、シノズカ(Shi nozuka)、
K。
S、、マクバーランド(McPar 1and)、に、B、、 バイアマン(H
yerman)、におよびTs′O,P、O,P、。
Biochemistr 20:1874〜1880(1981)];およびホ
スホロチオエート[セルノ(Ceruzzi)、Mおよびトレーパー(Drap
er)、に、、Nucleosides &Nucleotides 8:81
5〜818(1989);ミラー、p、s、。
ブライタ?ン、L、T、およびTs′O,P、O,P、。
Biochemi 5try 上6 :1988〜1996 (1977)およ
びローフ(Loke)、S、L、−スタイン(Stei n)、C,、ザング(
Zhang)、X、H,、エイビガン(Avigan)、M、、コーエン(Co
hen)、J、およびネッカーズ(Neckers)、L、M、。
Curr、Top、Microbiol、Immunol、141:282〜2
89 (1988)]を用いて研究された。
ホスホロチオエートは、各リン酸結合の酸素原子か硫黄で置換されているオリゴ
ヌクレオチド類似体て゛ある。全体の電荷は保持され、したかって、それらはホ
スホジエステルオリゴヌクレオチドとの関係において同等であるか、この種類の
類似体のいくつかの性質は、それらを他の修飾化合物よりも興味深いものにする
。
これらには、化学合成の容易さ、十分な水への溶解性、比較的高いヌクレアーゼ
耐性および相補的DNAまたはRNA9を有する安定な二重らせんを形成する能
力かある。しかしながら、ホスホロチオエートは、ローフ(Loke)ら、Pr
oc、Nat 1.Acad、Sc i、U、S、A、86 : 3473〜3
478(1989)によって天然化合物に関して同時に研究されており、それら
はそれらのヌクレアーゼ耐性ゆえに有用であることかできるので、それらはそれ
らの天然オリゴヌクレオチド対応物はど効率よく内在化<1nternaliz
ed)されていない。
ヌクレオチド化学の進歩により、オリゴヌクレオチドの3′および5′末端に官
能基を結合させて、特定の細胞種での細胞の取込みを増大させることか可能にな
った。従来の研究では、アジアログリコプロティン−ポリ(L−リシン)結合体
と複合したプラスミドDNAは、ガラクトース末端のアシアログリコプロティン
に対する独特の細胞表面受容体を含む肝細胞を標的とすることができることか示
された、ウー(Wu)、G、Y、およびウー(Wu)、C,H,。
旦土立立江立匹1且旦二ヱ λ7:887〜892 (1988)、 他(f)
グルー7”は、5′結合アルキル化剤および3′結合コレステロール残基を有す
るオリゴデオキシリボヌクレオチドを合成し、そしてこれらの修飾オリゴヌクレ
オチドが、ステロイド残基不含の対照化合物よりも効率よく細胞中に取込まれる
ことを確認した、シン(Zon)、G、 、念上上盈立亘且旦工X旦且旦土且旦
工土旦旦互二Antisense Tnhibitors of Gene旦五
三ニ1且旦土on 234〜247.J、S、コーエン(Cohen)監修(C
RCプレス(Pressiボカ・ラドン、FL、1989)、レツインガ−(L
etsinger)ら、Proc、Nat 1.Acad、Sc i、U、S。
A、86:653〜656 (1989)では、更に、コレステリル結合ホスホ
ロチオエートを合成しており、その抗HIV活性は同一配列を有する天然オリゴ
ヌクレオチドよりも有意に大きい。更に別の修飾としては、ポリ(L−リシン)
のみに対するオリゴヌクレオチドの結合がある、ステイーブンマン(Steve
nson)、M、およびアイヴアセン(Iversen)、P、L。
、、J、Gen、Vi ro 1.70 : 2673〜2682 <1989
)およびルメートル(Lemaitre)、M、 、ベイナート(Baynar
d)、B、およびルブリュ−(LeBleu)、B、、Proc、Natl、A
cad、Sci。
U、S、A、84 : 648〜652 (1987)、この修飾は、おそらく
は、多階イオン性ポリ(L−リシン)によって与えられた増大した細胞の取込み
ゆえに、研究された化合物の抗ウィルス活性を増大させた。
従来入手可能なアンチセンスオリゴヌクレオチドの活性は、実際の治療、研究ま
たは診断用に用いるのに十分ではなかった。この不十分の根拠はいくつか組合わ
されていると考えられる、すなわち、(1)標的RNAの二次および三次構造の
不完全な理解、(2)デリバリ−および取込みの低百分率、(3)他の細胞性成
分による反応性中枢の失活および(4)タンパク質産生の阻害に対する化学量論
的条件の必要性である。
化学的修飾によるアンチセンスオリゴヌクレオチドの細胞の取込みの増大は明ら
かな利点を有するであろう、更に、新規の修飾は、新規の化合物の増大した親油
性、一層大きい保持および増大した分布を導くことができる。特定の細胞内標的
部位でのオリゴヌクレオチドの濃度の増大は、望ましい効果を生じるのに少量の
薬剤しか必要がないので、結局はこれらの化合物の安全性および有効性を増大さ
せることができる。
したがって、有効な治療および診断用アンチセンスの使用が可能であるオリゴヌ
クレオチドおよびオリゴヌクレオチド類似体、具体的には、細胞中への輸送を促
進する官能基から成り、同時に、ヌクレアーゼ活性に対して野生種はど感受性で
ないオリゴヌクレオチドまたはオリゴヌクレオチド類似体に対する必要性は長い
間感じられていたし、そしてなお続いている。この長い間感じられていた必要性
は、アンチセンスオリゴヌクレオチド療法および診断法の分野での先行研究によ
って満たされなかった。
発明の要約
本発明により、細胞の取込みを増大させるように修飾されている新規の種類のア
ンチセンスオリゴヌクレオチドを提供する。ポリアミンに対する直接結合によっ
て修飾された少なくとも1個のヌクレオシドを有するオリゴヌクレオチドは、こ
の目的を達成するのに有効であることか分かった。ヌクレオシドをその糖残基の
5′位でポリアミンに結合させるのが好ましい。本発明によるオリゴヌクレオチ
ドは、ホスホロチオエートまたは池の主鎖が修飾された種であるように修飾され
るのが好ましい、オリゴヌクレオチドは、好ましくは、長さが約5〜約50核酸
塩基であることができる0本発明の好ましい実施態様により、オリゴヌクレオチ
ドはHIVゲノムのtat領域をコードする。他の好ましい実施態様により、H
IVゲノムのtat領域をコードする選択された配列はその5′末端にチミジン
を有する。他の好ましいアンチセンスオリゴヌクレオチド配列としては、ヘルペ
ス、パピローマおよび他のウィルスに相補的な配列かある。
ホスホロチオエートオリゴヌクレオチドの5′末端で見出されるのか好ましい修
飾ヌクレオシドは、何等かのピリミジンまたはプリンであることかできる。しか
しながら、本発明の好ましい実施態様は、修飾されたチミジンを5′末端に包含
する。
修飾ヌクレオシドは、その糖残基の5′位でヌクレオシドに結合したポリアミン
上の官能基のヌクレアーゼ耐性結合であるのが好ましい、ポリアミン官能基は、
第一アミン、ヒドラジン、セミカルバジン、チオセミカルバジンまたは類似の窒
素含有種を含むことができる。ポリアミンの好ましい立体配置は、ポリアミンの
末端の官能基に関して各アミン機能毎に対称的炭素スペース基を包含する。
修飾ヌクレオシドおよびポリアミン官能基間の結合は、概して、当該技術分野で
現在知られている官能付加基ではないのか好ましい0通常のホスホジエステル結
合よりもむしろ、付加が直接5′位で生じる。この結合は、それがヌクレアーゼ
耐性であるという理由で当該技術分野の現在の状況にまさる改良であるのみなら
す、付加におけるオリゴヌクレオチドまたはオリゴヌクレオチド類似体へのこの
官能基の直接結合は、天然に存在するオリゴヌクレオチドに相対して優れた細胞
の取込みを与える。この優れた細胞の取込みは、ポリアミンを、オリゴヌクレオ
チド結合体の糖−リン酸主鎖並びにポリアミン−オリゴヌクレオチドへテロ二本
鎖の主鎖に沿って逆に向けることができるので、ポリアミンがオリゴヌクレオチ
ドの陰電荷を有する中和作用のためと考えられる。
本発明は、更に、このようなオリゴヌクレオチドを合成する方法、例えば、前述
の好ましい実施態様のものなどの適当な官能基と反応するように活性化すること
ができる中間生成物の合成を含む経路に関する。これらの方法は、活性化が生じ
る固体支持体を用いる。固体支持体のこのような使用は、DNA合成機によるか
または固体支持体の手動操作若しくはそれ以外によることができる。
発明の目的
本発明の主な目的は、アンチセンスオリゴヌクレオチド診断法、研究用試薬およ
び治療法において用いるためのオリゴヌクレオチド類似体を提供することである
。
本発明の更に別の目的は、増大した細胞の取込みを有するヌクレアーゼ耐性オリ
ゴヌクレオチド類似体を提供することである。
本発明のもう一つの目的は、天然に存在するアンチセンスオリゴヌクレオチドよ
りも治療学的に安全であり且つ有効性が大きいこのようなオリゴヌクレオチド類
似体を提供することである。
本発明の更にもう一つの目的は、固体支持体を用いる修飾オリゴヌクレオチドの
合成法を提供することである。
これらのおよび他の目的は、本明細書の論評から当業者に明らかになるものであ
る。
図面の簡単な説明
図1は、本発明の実施において有用な若干のポリアミン官能基の合成に有用なあ
る種の合成スキームのフローチャートである。
図2は、本発明において有用なポリアミン結合ホスホロチオエートオリゴヌクレ
オチドの合成の一つの方法を示す。
発明の詳細な説明
従来入手可能なアンチセンスオリゴヌクレオチドの生物学的活性は、概して、実
際の治療、研究または診断に用いるのに十分ではなかった7本発明はそれ自体、
修飾された天然に存在するオリゴヌクレオチドおよび類似木並乙(にこのような
修飾を行うための方法を指示する。これらの修飾オリゴヌクレオチドおよびオリ
ゴヌクレオチド類似体は、それらの天然に存在する対応物に相対して増大した生
物学的活性を示す。更に、これらの修飾は、当業者に一般的に知られている方法
方法論を用いて手動によって操作するかまたはDNA合成機と連結して用いるこ
とかできる固体支持体を用いて行うことかできる。
本発明の文脈において、「オリゴヌクレオチドJという用語は、本来のホスホジ
エステル結合によって糖基を介して結合した天然に存在する複素環式塩基および
フラノシル糖基から特異的配列で生成された複数の結合したヌクレオチジ単位を
意味する。これらのヌクレオチド巣位は、核酸塩基、例えば、グアニン、アデニ
ン、シトシン、チミンまたはウラシルであることができる。糖基はデオキシリボ
ースまたはりボーヌ糖であることができる。この用語は、天然に存在する種また
は天然に存在するサブユニットから生成された合成種双方を意味する。
本発明に関連して用語を用いる場合の「オリゴヌクレオチド類似体」は、オリゴ
ヌクレオチドと同様に機能するが、天然に存在する部分を有していない残基を意
味する。オリゴヌクレオチド類似体は、変更された糖残基または糖内結合、例え
ば、ホスホロチオエートおよび当該技術分野で用いるのに知られている池の硫黄
含有種を有することができる。オリゴヌクレオチド類似体は、更に、特定のオリ
ゴヌクレオチドをアンチセンス療法、診断用または研究用試薬に用いることを容
易にするために、変更された塩基巣位まなは本発明の精神と矛盾しない他の修飾
を含むことができる。
本発明により、概して、最終的に合成が調節さ?Lまたは完全に阻害されるタン
パク質の産生に関r系しているDNaまたはRNAに対して相補的であるオリゴ
ヌクレオチド配列か選択される6本発明の一つの好ましい実施態様は、HIVの
tat領域をコードするD N 、A 、:なはRNAに対して相補的なアンチ
センスオリゴヌクレオチド類似体である。eの好ましい実施態様はヘルペスおよ
びパピローマウィルスに関するが、なお他は当業者に明らがである。
更に、本発明の好ましい実施態様により、ホスホロチオエート結合を、オリゴヌ
クレオチドの糖リン酸主祭を通常含むホスホジエステル結合に代用する。これら
のオリゴヌクレオチド類似体を、それらの末端の5′末端でヌクレオシドの付加
によって更に修飾するのが好ましいにのヌクレオシド類似体は修飾チミジンであ
るのか最も好ましい。前記の修飾ヌクレオシドは、チミジンの糖残基の5′位で
・のような保護基の付加を更に含むことができる。本発明の一つの好ましい実施
態様による保護基は1.3−ジフェニルイミダゾリニル基である。
オリゴヌクレオチド類似体中に包含された修飾ヌクレオシド類似体を、窒素含有
官能基を有するそのlli残基の5′位での保護基の置換によって更に修飾する
のが好ましい、窒素含有官能基は、第一アミン、ヒドラジン、セミカルバジド、
チオセミカルバジドまたはアルデヒド性機能と反応することができる他の基など
の末端官能基を有するポリアミンであるのが好ましいが、図1に示したようなポ
リアミン8またはポリアミン10の構造を有するポリアミンであるのが好ましい
。
窒素含有官能基と修飾ヌクレオシドのアルデヒド性基との反応後に、中間体シッ
プ塩基(イミン)、ヒドラジンまたはセミカルバゾンを還元して置換アミン、ヒ
ドラジンまたはセミカルバジドにする。最も好ましい窒素含有官能基は図1に示
したようなポリアミン10の構造を育する。
したがって、好ましいポリアミンは、一般式%式%
(式中、Xは第一アミン、ヒドラジン、セミカルバジドまたはチオセミカルバジ
ドであり且つnは2〜6の整数である)を有する。
より一層好ましいポリアミンは、一般式HN(CH) NH(CH) NH(C
H2)nNH−22n 2n
(式中、nは2〜6の整数である)
を有する。nは4であるのが好ましい。
理論に束縛されたくはないが、正に荷電しているポリアミンは、オリゴヌクレオ
チドの陰電荷の糖−リン酸主鎖に沿って位置していると考えられる。この立体配
置は、オリゴヌクレオチドの陰電荷を中和し且つオリゴヌクレオチドの細胞透過
を増大させると考えられる。いくつかの最近の報告は、ポリアミンが主溝の塩基
対の末端に水素結合を生成することがあることを示唆した、ローフ(Loke)
、S、L、 、スタイン(Ste in)、C,A、 、ザング(Zhang)
、X。
Hl、そり(Mori)、に、 、ナカニシ(Nakanishi)、M、 、
スバシンギ(Subashi nghe)、G1、コーエン(Choen)、J
、S。
およびネッカース(Neckers)、L、M、、Proc、Nat l。
Acad、Sc t、U、S、A、86 : 3473〜3479 (1989
)、この問題を避けるために、本発明は、ホスホジエステル結合を介するポリア
ミンの結合を用いないのが好ましいが、その代わりにポリアミンを直接5′位に
結合させる。ホスホジエステル結合を結合リンカ−として除去し且つポリアミン
を直接5′位に結合させることによって、オリゴヌクレオチド結合体の糖すン酸
主鋳並びにポリアミン−オリゴヌクレオチドへテロ二本鎖に沿った逆のポリアミ
ン鎖を支配する強い性質が存在すると考えられる。
本発明の好ましい実施態様は、各アミン毎に約4個の炭素単位を有するポリアミ
ンを用いる。炭素スペーサーは、アミン基との関係において種々の立体配置で配
列することができる。この配列は、オリゴヌクレオチドおよびそのヘテロ二本鎖
のポリアミンの部位存在を支配するのに有用であることができる。結合したオリ
ゴヌクレオチドおよびそれらのへテロ二本鎖のある位置にポリアミンが存在する
ように支配するこの能力は、オリゴヌクレオチド取込みおよび他のオリゴヌクレ
オチドの性質に関係がある重要性を有すると考えられる。他の多数の炭素単位は
、本発明による好ましいポリアミンの窒素原子間に間隔を置くことができる。
当業者は、特定の状況に最適の立体配置を選択する場合に広範な許容範囲を有し
、例えば、2個、5個、6個または他の個数の炭素単位を用いることができる。
本発明のある態様により、図2は、修飾ホスホルアミダイトオリゴヌクレオチド
類似体の一つの化学合成法を示す。特に、図2は、1,3−ジフェニルイミダゾ
リジン保護5′−アルデヒド性−3’−(2−シアノエチル−N、N−ジイソプ
ロピルホスホルアミジチル)チミジンの合成に関係した新規の方法を示す、この
塩基安定性のチミジン類似体を望ましいオリゴヌクレオチド配列の5′末端に置
き、必要ならば活性化して、第一アミン、ヒドラジン、セミカルバジドまたはチ
オセミカルバジドなどのポリアミンを結合する。
図2で示した方法によって用いた出発物質は、ツイツテ−(Pfitzner)
およびモファット(Moffatt)、フイツナー、に、E、ら、止工Amer
ican、Chem、Soc、85:3027 (1963)の方法によってま
たはその方法の明らかな変更によって高収率で製造することができるテオキシリ
ホフラノシルまたはリボフラノシルヌクレオシドである。この方法は、3′−ア
セチルチミジンの酸化反応を記載している。修飾されるヌクレオシドのアセチル
誘導体も、適当な出発物質であることができる。このようなアセチル誘導体は商
業的に入手することができるしまたは当業者に知られている方法を用いて三工程
法で製造してもよい。
このアセチル化法の第一工程は、ヌクレオシドをブロックするための塩化t−ブ
チルジメチルシリル(TBDMSCl )と選択されたヌクレオシドとの反応で
ある0次に、無水酢a(Ac O)を加えた後、B u 4 Fを加えて、選択
されたヌクレオシドの最終のアセチル誘導体を生成する0本発明の好ましい実施
態様により、この三工程法を用いてチミジン(出発物質)を3′−アセチルチミ
ジンに変換する。或いは、市販の3′−アセチルチミジンを利用する。
続いて、3′−アセチルヌクレオシド(14)をDMSO/DCCで処理するこ
とによって酸化した後、1.2−ジアニリノエタンで処理して3′−〇−アセチ
ルー5′−デオキシー5′−(1,3−ジフェニルイミダシリン−2−イル)ヌ
クレオシド(16)を生成する。この保護基は塩基性条件に対して安定であるこ
とが分かったし、そして弱酸を用いて加水分解してアルデヒドに戻すことができ
る。この機能を達成するのに有用な、既存のまたはこれから発見される任意の基
を、本発明の実施にしたかって用いることかて゛きる。好ましい実施態様により
、3′−〇−アセチルー5′−デオキシー5′−(1,3−ジフェニルイミダシ
リン−2−イル)チミジンは、3′−アセチルチミジンをDMSO/DCCで処
理した後、1.2−アニリノエタンで処理することから得られる。
アセチル基の脱プロンキングに続いて、保護されたアルデヒド性ヌクレオシドを
標準法によってホスホルアミダイト(18)に変換する6例えば、アセチル基は
、N H3/’ M e OHを加えた後に、引き続きホスフィチルCIを加え
ることによるホスフィチル化によって除去される。好ましい方法は、2−シアン
エチル−N、N−ジイソプロピルクロロホスホルアミタイトを加えることによる
ホスフィチル化である6例えば、好ましい実施態様により、3′−〇−アセチル
ー5′−デオキシー5′−(1,3−ジフェニルイミダシリン−2−イル)チミ
ジンを脱ブロッキングした後、5′−デオキシ−5′−(ジフェニルイミダゾリ
ン−2−イル)チミジン−2−シアノエチル−N、N−ジイソプロピルホスホル
アミタイトに変換する。
別個に、予め選択された配列を有するホスホロチオエートオリゴヌクレオチドを
、前記で製造されたような特定の修飾ヌクレオシドに対応するヌクレオシドがオ
リゴヌクレオチド配列中に包含される必要がある点まで、固体支持体上で5′方
向に延長する。修飾ヌクレオシドをその天然に存在する末端のヌクレオシド6二
代用して、オリゴヌクレオチド類似体(20)を生じる。最も好ましくは、修飾
チミジンはその天然に存在する対応物を5′末端で置換する。
オリゴヌクレオチド合成法は、便宜上、既知のホスホルアミダイト方法論を用い
る固相状態合成法によってDNA合成iまたはそれ以外で行うことかできる。
核酸合成機は商業的に入手可能であり、概して、それらの使用は、望まれること
がある適度な長さのほとんど全部のオリゴヌクレオチドを生じるのに有効である
と当業者によって理解される。このようなオリゴヌクレオチド鎖は、長さが約5
〜約50核酸塩基であることができる。このような官能基は8〜約40塩基単位
を有するのが更に好ましく、約12〜20塩基単位を用いるのがより一層好まし
い、現在のところ一約15塩基単位を有する万すゴヌクレオチド類似体が、本発
明のある実施態様の実施に最もよいことか分かったと考えられている。
本発明の好ましい実施態様によると、HIVのtat領域は5′方向に延長され
て、配列CCGCCCCTCGCCTCTTGCCTを生じるか、それは、この
領域か、tatタンパク質の発現を阻害するのに最も強力な活性を有すると考え
られるためである。本明細書中に参考として包含される、1990年5月11日
出Hのおよび本発明の譲受人に譲渡された出願番号第521907号明細書を参
照されたい。次に、その配列を、5′末端のTヌクレオチドを考慮するように、
3種類の別のヌクレオチドをTCGCCGCCCCTCGCCTCTTGCCT
に延長するのか好ましい。チミジン残基は前記に記載しなように、ジフェニルイ
ミダゾリニルチミジンで置換された。
得られたホスホルアミタイト結合は、好ましくは、既知のビューケージ(Bea
ucage)試薬二ビューケージ、S、L、ら、J、Am、Chem。
Soc、112:1253〜1254 (1990)]を用いて硫化して、好ま
しいホスホロチオエートを与えることができるしまたはヨウ素によってホスホジ
エステル結合を与えることかできる0例えば、図2のXは酸素または硫黄である
。
窒素含有官能基、好ましくは、末端第一アミン、ヒドラジン、セミカルバジドま
たはチオセミカルバジドを包含するものなどのポリアミンの付加は、好ましくは
、修飾ヌクレオシドがホスホルアミダイトオリゴヌクレオチドに加えられたなら
ば行うことかできる。この付加の第一工程は、オリゴヌクレオチドの5′末端に
加えられた修飾ヌクレオシドのアルデヒド性基の脱保護である。この脱保護は、
修飾ヌクレオシド含有オリゴヌクレオチドを、(合成機中でホスホルアミダイト
オリゴヌクレオチドを結合する)制御細孔ガラス(CPG)支持体上においてT
HF中の3%ジクロロ酢酸(DCA)で処理することによる好ましい実施態様に
よって生じることができる。続いて、CPG支持体上の修飾ヌクレオシド含有オ
リゴヌクレオチドをポリアミンで処理してシップ塩基(イミン)を生成する。シ
ップ塩基は、ナトリウムシアノポロハイドライド(NaCHBH3)を加えるこ
とによってアミンに還元される。最終的に、CPG支持体を水酸化アンモニウム
で処理して脱保護し、そしてポリアミン−オリゴヌクレオチド結合体(22)を
支持体から除去する。
CPG支持体の処理は、DNA合成機によってまたは手動によってシリンジを用
いて行うことかできる1本発明の実施態様に好ましい官能基はポリアミンである
。最も好ましくは、本発明の他の好ましい成分との組み合わせで有用なポリアミ
ン官能基はトリス(アミノブチル)アミンである。このポリアミンは、好ましい
長さゆえに選択された。この基のアミン−炭素結合の長さは、分子模型に基づい
たおよそ15塩基対のオリゴヌクレオチドの長さに及ぶ。
各アミン毎に置かれた炭素スペーサーは、結合したオリゴヌクレオチドのある位
置にポリアミンか存在するように指示するのに有用であることができる。好まし
くは、炭素スペーサーを、炭素スペース基が対称的であるように配列させる。
各アミン毎に置かれた4個の炭素スペーサーは、本発明の好ましい実施態様であ
る。
ポリアミン基の合成は、当該技術分野で知られている方法によって行うことかで
きる。好ましい実施態様に対して、ポリアミン基の合成は、図1に示した工程に
したがって行うことができる。トリス(アミノブチル)アミン(7)または飴の
類似のアミンは、参考として本明細書中に包含される、ニイツ(Niitsu)
およびサメシマ(Samej ima)+ Chem、Pharm、Bu I
I 、34工旦):1032〜1038 (1986)に記載された方法によっ
て合成することができる。このようなアミンは、例えば、ミラーおよびブライタ
マンら、Biochemistr 上6 :1988〜1996 (1977)
に示された、TNDPS−CIおよびEt3Nの付加を必要とする方法にしたが
って、それらの第一アミノ基の一つにt−ブチルジフェニルシリル基を用いて保
護される。得られたt−ブチルジフェニルシリルアミン(8)は修飾オリゴヌク
レオチドとの反応に好都合なアミンである。しかしながら、更に好ましくは、修
飾オリゴヌクレオチドと結合する前に、化合物(8)を、Et2N中の酢酸トリ
フルオロエチルを用いるトリフルオロアセチル化によって更に修飾した後、ピリ
ジニウム水素フッ化物を用いてt−ブチルジフェニルシリル残基を選択的に除去
してTFA保護アミン(10)を与える。この脱保護工程は、オーヴアマン(○
verman)ら、Tetrahedron Lett、27:4391〜43
94 (1986)に記載されている。全工程は、全収率か高い種々のポリアミ
ンの合成法に従う。
記述した参考文献はいずれも参考として本明細書中に包含される。
変法において、ヌクレオシドの5′アルデヒドは、トリフルオロアセチル保護ポ
リアミンと縮合することかできる。ナトリウムシアノボロハイドライドによるシ
ッフ塩基の引き続きの還元および3′位のホスフィチル化は、保護されたポリア
ミンモノマーを与える。この保護ポリアミンモノマーを、DNA合成機によって
オリゴヌクレオチドの5′末端に結合することができる。
ポリアミン−オリゴヌクレオチド結合体のカラムからの脱保護および除去は、カ
ラムを水酸化アンモニウムで処理することによって行うことかできる。最終的に
、組成物は、高速液体クロマトグラフィーおよびゲル電気泳動システムを用いて
精製することができる。このような精製方法は当業者に周知である。
下記の実施例は本発明を例証するものであるが、制限するものではない。
実施例
実施例1
1、 <3′−0−アセチル−1,3−ジフェニルイミダシリン−2−イル)ヌ
クレオシドの製造
標準法によって製造された3′−〇−アセチルチミジン(1,0g)を、DCC
(3,63g)およびDMSO5ml中にH3PO4が0.49gのアリコー)
1.8mlのDMSO(20ml )中撹拌混合物に窒素雰囲気下で加えた。そ
の混合物を室温で一晩中撹拌した。溶媒を除去し、そしで残留物を石油エーテル
と水とに分配した。有機相をストリップし、そして残留物をMeOH(20ml
>中に溶解させた。ジアニリノエタン(0,0047mM、1.0g)を加え
、そして反応を一晩中撹拌して、3′−〇−アセチルー5′−デオキシー5′−
(1゜3−ジフェニルイミダシリン−2−イル)チミジンを生じた。
2、 3−ホスホルアミダイトヌクレオシド3′−〇−アセチルー5′−デオキ
シー5′−(1,3−ジフェニルイミダシリン−2−イル)チミジンを、塩基脱
保護の標準法を用いた後にホスホルアミタイトホスフィチル化を用いて、メタノ
ール性アンモニアで脱アセチル化し、そして2−シアノエチル−N、N−ジイソ
プロピルクロロホスホルアミタイトでホスフィチル化して、5′−デオキシ=5
′−(1,3−ジフェニルイミダゾリン−2−イル)チミジン−2−シアンエチ
ル−N、N−ジイソプロピルクロロホスホルアミダイトを生成する。
3、 オリゴヌクレオチド配列の製造
配列5’ CCGCCCCTCGCCTCTTGCCT3 ′を有する活性HI
Vホスホロチオエートオリゴヌクレオチドのtat領域を、標準的な自動合成法
を用いてABI型380B−I)NA合成機で5′方向に増成した。3種類の更
に別のヌクレオチドを加えてその配列を延長して、5′−チミジン末端配列、す
なわち、末端のチミジンヌクレオチドが5′−デオキシ−5′−(ジフェニルイ
ミダゾリン−2−イル)チミジンで置換した配列5’ TCGCCGCCCCT
CGCCTCTTGCCT3 ′にした。
4、 ポリアミンの製造
トリス(アミノブチル)アミンを、当業者に知られている標準法によって製造す
る。
5、 ポリアミンの付加
実施例1−1の方法のホスホルアミダイト結合オリゴヌクレオチドを、ビューケ
ージ試薬を用いて硫化する、ビューケージ、S、L、ら、J、Am、Chem。
Soc、112:1253〜1254 (1990)、次に、CPG支持体を、
THF中の3%ジクロロ酢酸で処理してアルデヒド性保護基を除去する0次に、
CPG支持体をトリス(トリフルオロアセチル)トリス(アミノブチル)アミン
で引き続き処理して、末端アルデヒドとアミンの間にシッフ塩基を生成する0次
に、ナトリウムシアノボロハイドライド(NaCHBH3)を加えて結合体を還
元してアミンにする。カラムを水酸化アンモニウムで処理して脱保護し且つ結合
体をカラム支持体から除去する。ポリアミン結合体を、ベックマン・ゴールド(
Beckman Gold)高速液体クロマトグラフィーシステムを用いるイオ
ン交換高速液体クロマトグラフィーおよびケル電気泳動によってwI製する。
実施例2
実施例1に示したプロトコルを用いて、パピローマウィルスmRNAキャップ領
域のアンチセンスホスホルアミタイトオリゴヌクレオチドである5’ TATG
CAAGTACAAAT3 ′の合成を行う。
実施例3
実施例1に示したプロトコルを用いて、パピローマウィルス翻訳開始配列のアン
チセンスホスホルアミタイトオリゴヌクレオチドである5’ TCTCCATC
CTCTTCACT3 ′の合成を行う。
実施例4
実施例1に示したプロトコルを用いて、ヘルペスウィルのアンチセンスホスホル
アミダイトオリゴヌクレオチド配列である5’ TCATCCATCCTTCG
GCC3’の合成を行う。
実施例5
実施例1に示したプロトコルを用いて、ヘルペスウィルのアンチセンスホスホル
アミダイトオリゴヌクレオチド配列である5 ′TGGCCATTTCAACA
GA3 ′の合成を行う。
実施例6
実施例1に示したプロトコルを用いて、ヘルペスウィルのアンチセンスホスホル
アミダイトオリゴヌクレオチド配列である5 ′TCATCCATCCGTCC
GCC3′の合成を行う。
実施例7
実施例1に示したプロトコルを用いて、ヘルペスウィルのアンチセンスホスホル
アミダイトオリゴヌクレオチド配列である5′TTGGCCATTGGAACC
AA3′の合成を行う。
8 − 82N(CH2)4NH(CH2)4NH(CH2)4NH−TBDP
SF/GURE/
FIGURE2
国際調査報告
I″m^“1111v 、テ/ll5OI /n&nllAフロントページの続
き
(51) Int、 C1,5識別記号 庁内整理番号Cl2N 15/11
ZNA
I
Claims (39)
- 1.ポリアミンに対する直接結合によって修飾された少なくとも1個のヌクレオ シドを有するオリゴヌクレオチド類似体。
- 2.オリゴヌクレオチド類似体の長さが約5〜約50ヌクレオチド塩基単位であ る請求項1に記載のオリゴヌクレオチド類似体。
- 3.前記のオリゴヌクレオチド類似体がアンチセンス治療薬として有用である請 求項1に記載のオリゴヌクレオチド類似体。
- 4.前記のヌクレオシドがその糖残基の5′位でポリアミンに結合している請求 項1に記載のオリゴヌクレオチド類似体。
- 5.前記のヌクレオシドがチミジンである請求項1に記載のオリゴヌクレオチド 類似体。
- 6.前記のポリアミンがそこに、アミン官能基、ヒドラジン官能基、セミカルバ ジド官能基またはチオセミカルバジド官能基を含む請求項1に記載のオリゴヌク レオチド類似体。
- 7.HIVゲノムのtat領域と特異的にハイブリッド形成しうる選択された配 列を含む請求項1に記載のオリゴヌクレオチド類似体。
- 8.前記の選択された配列がその5′末端にチミジンを有する請求項7に記載の オリゴヌクレオチド類似体。
- 9.ヘルペスゲノムの選択された部分と特異的にハイブリッド形成しうる選択さ れた配列を含む請求項1に記載のオリゴヌクレオチド類似体。
- 10.パピローマゲノムの選択された部分と特異的にハイブリッド形成しうる選 択された配列を含む請求項1に記載のオリゴヌクレオチド類似体。
- 11.前記のポリアミンが構造 H2N(CH2)nNH(CH2)nNH(CH2)nNH−(式中、nは2〜 6の整数である) を有する請求項1に記載のオリゴヌクレオチド類似体。
- 12.nが4である請求項11に記載のオリゴヌクレオチド類似体。
- 13.少なくとも1個のホスホロチオエート基を含む請求項1に記載のオリゴヌ クレオチド類似体。
- 14.少なくとも1個のヌクレオシドが、ポリアミンに対する直接結合によって 修飾されているアンチセンスオリゴヌクレオチド類似体を合成する方法であって 、 約5〜約50ヌクレオチド塩基の選択された配列を有するオリゴヌクレオチドを 、選択された修飾ヌクレオシドが包含されることになっている該配列のある点ま で、固体支持体上において5′方向に延長し;ヌクレオシドを該オリゴヌクレオ チド配列中に包含し;そしてポリアミンを該ヌクレオシドの5′位に直接結合さ せることを含む上記の方法。
- 15.前記のポリアミンを、前記のヌクレオシドが前記のオリゴヌクレオチド中 に包含された後に、前記のヌクレオシドに結合させる請求項14に記載の方法。
- 16.前記のポリアミンを、前記のオリゴヌクレオチド中への前記のヌクレオシ ドの前記の包含の前に、該ヌクレオシドに結合させる請求項14に記載の方法。
- 17.前記のヌクレオシドがチミジンである請求項14に記載の方法。
- 18.前記のポリアミンがそこに、第一アミン官能基、ヒドラジン官能基、セミ カルバジド官能基またはチオセミカルバジド官能基を含む請求項14に記載の方 法。
- 19.前記の製造工程が、前記のヌクレオシドを前記のオリゴヌクレオチドに包 含する前に、前記のヌクレオシド上の保護基を加え;そして前記のポリアミンを 該ヌクレオシドに結合する前に、該ヌクレオシドを脱保護する工程を更に含む請 求項14に記載の方法。
- 20.前記のポリアミンが構造 H2N(CH2)nNH(CH2)nNH(CH2)nNH−(式中、nは2〜 6の整数である) を有する請求項14に記載の方法。
- 21.前記のオリゴヌクレオチドがホスホロチオエートオリゴヌクレオチドであ る請求項14に記載の方法。
- 22.生物によるタンパク質の産生を調節する方法であって、該タンパク質をコ ードする選択された配列と特異的にハイブリッド形成しうる、少なくとも1個の ヌクレオシドがポリアミンに対する直接結合によって修飾されているオリゴヌク レオチド類似体と該生物を接触させることを含む上記の方法。
- 23.オリゴヌクレオチドがホスホロチオエート結合を含む請求項22に記載の 方法。
- 24.オリゴヌクレオチドが約5〜約50ヌクレオチド塩基を含む請求項22に 記載の方法。
- 25.前記のヌクレオシドを、その糖残基の5′位でポリアミンに結合させる請 求項22に記載の方法。
- 26.前記のヌクレオシドがチミジンである請求項22に記載の方法。
- 27.前記のポリアミンがそこに、第一アミン官能基、ヒドラジン官能基、セミ カルバジド官能基またはチオセミカルバジド官能基を含む請求項22に記載の方 法。
- 28.前記のポリアミンが構造 H2N(CH2)nNH(CH2)nNH(CH2)nNH−(式中、nは2〜 6の整数である) を有する請求項22に記載の方法。
- 29.nが4である請求項28に記載の方法。
- 30.疾患を有する生物を治療する方法であって、RNAまたはDNAの選択さ れた配列と特異的にハイブリッド形成しうるオリゴヌクレオチド類似体であって 、その少なくとも1個のヌクレオシドがポリアミンに対する直接結合によって修 飾されているオリゴヌクレオチド類似体と該生物を、単独でかまたは薬学的に許 容しうる担体との組合わせで接触させることを含む上記の方法。
- 31.前記のヌクレオシドを、その糖残基の5′位でポリアミンに結合させる請 求項30に記載の方法。
- 32.前記のヌクレオシドがチミジンである請求項30に記載の方法。
- 33.前記のポリアミンがそこに、第一アミン官能基、ヒドラジン官能基、セミ カルバジド官能基またはチオセミカルバジド官能差を含む請求項30に記載の方 法。
- 34.前記の選択された配列がHIVゲノムのtat領域をコードする請求項3 0に記載の方法。
- 35.前記の選択された配列がその5′末端にチミジンを有する請求項30に記 載の方法。
- 36.前記の選択された配列がヘルペスゲノムの選択された部分をコードする請 求項30に記載の方法。
- 37.前記の選択された配列がパピローマゲノムの選択された部分をコードする 請求項30に記載の方法。
- 38.前記のポリアミンが構造 H2N(CH2)nNH(CH2)nNH(CH2)nNH−(式中、nは2〜 6の整数である) を有する請求項30に記載の方法。
- 39.nが4である請求項38に記載の方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US558,663 | 1990-07-27 | ||
US07/558,663 US5138045A (en) | 1990-07-27 | 1990-07-27 | Polyamine conjugated oligonucleotides |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH06500087A true JPH06500087A (ja) | 1994-01-06 |
Family
ID=24230444
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP3513696A Pending JPH06500087A (ja) | 1990-07-27 | 1991-06-10 | 新規のポリアミン結合オリゴヌクレオチド |
Country Status (9)
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---|---|
US (1) | US5138045A (ja) |
EP (1) | EP0544757B1 (ja) |
JP (1) | JPH06500087A (ja) |
AT (1) | ATE159025T1 (ja) |
AU (1) | AU649067B2 (ja) |
BR (1) | BR9106701A (ja) |
CA (1) | CA2087731A1 (ja) |
DE (1) | DE69127903T2 (ja) |
WO (1) | WO1992002531A1 (ja) |
Families Citing this family (843)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5242794A (en) * | 1984-12-13 | 1993-09-07 | Applied Biosystems, Inc. | Detection of specific sequences in nucleic acids |
CA2001401A1 (en) * | 1988-10-25 | 1990-04-25 | Claude Piantadosi | Quaternary amine containing ether or ester lipid derivatives and therapeutic compositions |
US5859221A (en) * | 1990-01-11 | 1999-01-12 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
US20040142899A1 (en) * | 1990-01-11 | 2004-07-22 | Isis Pharmaceuticals, Inc. | Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals |
US7037646B1 (en) | 1990-01-11 | 2006-05-02 | Isis Pharmaceuticals, Inc. | Amine-derivatized nucleosides and oligonucleosides |
US5635488A (en) * | 1991-10-15 | 1997-06-03 | Isis Pharmaceuticals, Inc. | Compounds having phosphorodithioate linkages of high chiral purity |
US5587361A (en) * | 1991-10-15 | 1996-12-24 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US6339066B1 (en) | 1990-01-11 | 2002-01-15 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides which have phosphorothioate linkages of high chiral purity and which modulate βI, βII, γ, δ, Ε, ζ and η isoforms of human protein kinase C |
US6753423B1 (en) | 1990-01-11 | 2004-06-22 | Isis Pharmaceuticals, Inc. | Compositions and methods for enhanced biostability and altered biodistribution of oligonucleotides in mammals |
US5959096A (en) * | 1992-03-16 | 1999-09-28 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against human protein kinase C |
US6358931B1 (en) | 1990-01-11 | 2002-03-19 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulating RNA |
US6399754B1 (en) * | 1991-12-24 | 2002-06-04 | Isis Pharmaceuticals, Inc. | Sugar modified oligonucleotides |
US5620963A (en) * | 1991-10-15 | 1997-04-15 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating protein kinase C having phosphorothioate linkages of high chiral purity |
US6783931B1 (en) | 1990-01-11 | 2004-08-31 | Isis Pharmaceuticals, Inc. | Amine-derivatized nucleosides and oligonucleosides |
US5872232A (en) * | 1990-01-11 | 1999-02-16 | Isis Pharmaceuticals Inc. | 2'-O-modified oligonucleotides |
US6005087A (en) * | 1995-06-06 | 1999-12-21 | Isis Pharmaceuticals, Inc. | 2'-modified oligonucleotides |
US5834607A (en) * | 1990-07-27 | 1998-11-10 | Isis Pharmaceuticals, Inc. | Amines and methods of making and using the same |
US5783682A (en) * | 1990-07-27 | 1998-07-21 | Isis Pharmaceuticals, Inc. | Oligonucleotide mimics having nitrogen-containing linkages |
US5386023A (en) * | 1990-07-27 | 1995-01-31 | Isis Pharmaceuticals | Backbone modified oligonucleotide analogs and preparation thereof through reductive coupling |
US5541307A (en) * | 1990-07-27 | 1996-07-30 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogs and solid phase synthesis thereof |
US5602240A (en) * | 1990-07-27 | 1997-02-11 | Ciba Geigy Ag. | Backbone modified oligonucleotide analogs |
HU217036B (hu) * | 1990-08-03 | 1999-11-29 | Sanofi | Eljárás génexpresszió gátlására alkalmas vegyületek előállítására |
US6153595A (en) * | 1990-08-16 | 2000-11-28 | Isis Pharmaceuticals Inc. | Composition and method for treatment of CMV infections |
CA2092002A1 (en) * | 1990-09-20 | 1992-03-21 | Mark Matteucci | Modified internucleoside linkages |
US5965722A (en) * | 1991-05-21 | 1999-10-12 | Isis Pharmaceuticals, Inc. | Antisense inhibition of ras gene with chimeric and alternating oligonucleotides |
US7015315B1 (en) | 1991-12-24 | 2006-03-21 | Isis Pharmaceuticals, Inc. | Gapped oligonucleotides |
FR2679255B1 (fr) * | 1991-07-17 | 1993-10-22 | Bio Merieux | Procede d'immobilisation d'un fragment nucleique par fixation passive sur un support solide, support solide ainsi obtenu et son utilisation. |
US5661134A (en) * | 1991-10-15 | 1997-08-26 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating Ha-ras or Ki-ras having phosphorothioate linkages of high chiral purity |
US5576302A (en) * | 1991-10-15 | 1996-11-19 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating hepatitis C virus having phosphorothioate linkages of high chiral purity |
US5599797A (en) * | 1991-10-15 | 1997-02-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides having phosphorothioate linkages of high chiral purity |
US5654284A (en) * | 1991-10-15 | 1997-08-05 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating RAF kinase having phosphorothioate linkages of high chiral purity |
US5607923A (en) * | 1991-10-15 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Oligonucleotides for modulating cytomegalovirus having phosphorothioate linkages of high chiral purity |
US6335434B1 (en) | 1998-06-16 | 2002-01-01 | Isis Pharmaceuticals, Inc., | Nucleosidic and non-nucleosidic folate conjugates |
US8153602B1 (en) | 1991-11-19 | 2012-04-10 | Isis Pharmaceuticals, Inc. | Composition and methods for the pulmonary delivery of nucleic acids |
US5359044A (en) * | 1991-12-13 | 1994-10-25 | Isis Pharmaceuticals | Cyclobutyl oligonucleotide surrogates |
CA2131311C (en) * | 1992-03-05 | 2004-06-29 | Phillip Dan Cook | Covalently cross-linked oligonucleotides |
US6153599A (en) * | 1992-03-16 | 2000-11-28 | Isis Pharmaceuticals, Inc. | Methoxyethoxy oligonucleotides for modulation of protein kinase C expression |
US5882927A (en) * | 1992-03-16 | 1999-03-16 | Isis Pharmaceuticals, Inc. | Oligonucleotide inhibition of protein kinase C |
US6537973B1 (en) | 1992-03-16 | 2003-03-25 | Isis Pharmaceuticals, Inc. | Oligonucleotide inhibition of protein kinase C |
US5916807A (en) * | 1992-03-16 | 1999-06-29 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against human protein kinase C |
US5922686A (en) * | 1992-03-16 | 1999-07-13 | Isis Pharmaceuticals, Inc. | Oligonucleotide modulation of protein kinase C |
US5885970A (en) * | 1992-03-16 | 1999-03-23 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against human protein kinase C |
ATE212063T1 (de) * | 1992-03-16 | 2002-02-15 | Isis Pharmaceuticals Inc | Oligonukleotide modulation von protein kinase c |
US6117847A (en) * | 1992-03-16 | 2000-09-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides for enhanced modulation of protein kinase C expression |
US5948898A (en) * | 1992-03-16 | 1999-09-07 | Isis Pharmaceuticals, Inc. | Methoxyethoxy oligonucleotides for modulation of protein kinase C expression |
US5817781A (en) | 1992-06-01 | 1998-10-06 | Gilead Sciences, Inc. | Modified internucleoside linkages (II) |
US6174868B1 (en) | 1992-09-10 | 2001-01-16 | Isis Pharmaceuticals, Inc. | Compositions and methods for treatment of hepatitis C virus-associated diseases |
US6235886B1 (en) | 1993-09-03 | 2001-05-22 | Isis Pharmaceuticals, Inc. | Methods of synthesis and use |
AU4848793A (en) | 1992-09-11 | 1994-04-12 | Isis Pharmaceuticals, Inc. | Oligonucleotide and nucleotide amine analogs, methods of synthesis and use |
CA2105595A1 (en) * | 1992-09-23 | 1994-03-24 | Ramaswamy Narayanan | Antisense polynucleotides |
WO1994007367A1 (en) * | 1992-09-29 | 1994-04-14 | Apollon, Inc. | Anti-viral oligomers that bind polypurine tracts of single-stranded rna or rna-dna hybrids |
US6784290B1 (en) | 1992-10-05 | 2004-08-31 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide inhibition of ras |
US20030013670A1 (en) * | 1992-10-05 | 2003-01-16 | Monia Brett P. | Antisense oligonucleotide inhibition of ras |
US5985558A (en) * | 1997-04-14 | 1999-11-16 | Isis Pharmaceuticals Inc. | Antisense oligonucleotide compositions and methods for the inibition of c-Jun and c-Fos |
JP2739769B2 (ja) * | 1992-10-05 | 1998-04-15 | 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 | ras遺伝子のアンチセンスオリゴヌクレオチドによる阻害 |
US5872242A (en) * | 1992-10-05 | 1999-02-16 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide inhibition of ras |
US5512671A (en) * | 1993-02-16 | 1996-04-30 | Wake Forest University | Ether lipid-nucleoside covalent conjugates |
WO1994027615A1 (en) * | 1993-05-26 | 1994-12-08 | Genta Incorporated | Oligomer conjugates and their use |
ATE226437T1 (de) * | 1993-06-10 | 2002-11-15 | Univ Wake Forest | (phospho)lipide zum bekämpfen einer hepatitis b- infektion |
US5428149A (en) * | 1993-06-14 | 1995-06-27 | Washington State University Research Foundation | Method for palladium catalyzed carbon-carbon coulping and products |
EP0705335A1 (en) * | 1993-06-23 | 1996-04-10 | Genesys Pharma Inc. | Antisense oligonucleotides and therapeutic use thereof in human immunodeficiency virus infection |
US6294664B1 (en) | 1993-07-29 | 2001-09-25 | Isis Pharmaceuticals, Inc. | Synthesis of oligonucleotides |
US6653458B1 (en) | 1993-09-03 | 2003-11-25 | Isis Pharmaceuticals, Inc. | Modified oligonucleotides |
AU679566B2 (en) | 1993-09-03 | 1997-07-03 | Isis Pharmaceuticals, Inc. | Amine-derivatized nucleosides and oligonucleosides |
DE4331670A1 (de) * | 1993-09-17 | 1995-03-23 | Hoechst Ag | Neue Antisense-Oligonucleotide gegen HSV-1 sowie deren Herstellung |
US5801154A (en) * | 1993-10-18 | 1998-09-01 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of multidrug resistance-associated protein |
WO1995020404A1 (en) * | 1994-01-31 | 1995-08-03 | University Of Medicine & Dentistry Of New Jersey | Triplex-forming paired-ion oligonucleotides and methods for preparing and using same |
DE4408528A1 (de) * | 1994-03-14 | 1995-09-28 | Hoechst Ag | Peptid-Oligonucleotid-Derivate, deren Herstellung und Verwendung |
US6919441B2 (en) | 1994-03-14 | 2005-07-19 | Aventis Pharma Deutschland Gmbh | Polyamide-oligonucleotide derivatives, their preparation and use |
US5981731A (en) * | 1994-05-31 | 1999-11-09 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of B-raf gene expression |
US6391636B1 (en) | 1994-05-31 | 2002-05-21 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of raf gene expression |
CA2197319C (en) * | 1994-08-29 | 2009-01-27 | Louis S. Kucera | Lipid analogs for treating viral infections |
US7135584B2 (en) | 1995-08-07 | 2006-11-14 | Wake Forest University | Lipid analogs for treating viral infections |
EP0888128A2 (en) | 1995-02-10 | 1999-01-07 | The Worcester Foundation For Biomedical Research | Delivery of exogenous compounds |
US6420549B1 (en) | 1995-06-06 | 2002-07-16 | Isis Pharmaceuticals, Inc. | Oligonucleotide analogs having modified dimers |
US5959100A (en) | 1996-03-27 | 1999-09-28 | Nexstar Pharmaceuticals, Inc. | Pyrimidine nucleosides as therapeutic and diagnostic agents |
US5856099A (en) * | 1996-05-21 | 1999-01-05 | Isis Pharmaceuticals, Inc. | Antisense compositions and methods for modulating type I interleukin-1 receptor expression |
US5898031A (en) | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
US20040266706A1 (en) * | 2002-11-05 | 2004-12-30 | Muthiah Manoharan | Cross-linked oligomeric compounds and their use in gene modulation |
US20030044941A1 (en) | 1996-06-06 | 2003-03-06 | Crooke Stanley T. | Human RNase III and compositions and uses thereof |
US7812149B2 (en) | 1996-06-06 | 2010-10-12 | Isis Pharmaceuticals, Inc. | 2′-Fluoro substituted oligomeric compounds and compositions for use in gene modulations |
US9096636B2 (en) | 1996-06-06 | 2015-08-04 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US6111085A (en) | 1996-09-13 | 2000-08-29 | Isis Pharmaceuticals, Inc. | Carbamate-derivatized nucleosides and oligonucleosides |
US6001991A (en) * | 1996-10-04 | 1999-12-14 | Isis Pharmaceuticals Inc. | Antisense oligonucleotide modulation of MDR P-glycoprotein gene expression |
US6319906B1 (en) | 1996-12-31 | 2001-11-20 | Isis Pharmaceuticals | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
US6077833A (en) * | 1996-12-31 | 2000-06-20 | Isis Pharmaceuticals, Inc. | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
US7235653B2 (en) * | 1996-12-31 | 2007-06-26 | Isis Pharmaceuticals, Inc. | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
US20040023917A1 (en) * | 1996-12-31 | 2004-02-05 | Bennett C. Frank | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
US6576752B1 (en) | 1997-02-14 | 2003-06-10 | Isis Pharmaceuticals, Inc. | Aminooxy functionalized oligomers |
US6172209B1 (en) | 1997-02-14 | 2001-01-09 | Isis Pharmaceuticals Inc. | Aminooxy-modified oligonucleotides and methods for making same |
US6127533A (en) | 1997-02-14 | 2000-10-03 | Isis Pharmaceuticals, Inc. | 2'-O-aminooxy-modified oligonucleotides |
CA2294988C (en) | 1997-07-01 | 2015-11-24 | Isis Pharmaceuticals Inc. | Compositions and methods for the delivery of oligonucleotides via the alimentary canal |
US6809193B2 (en) | 1997-08-13 | 2004-10-26 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide compositions and methods for the modulation of JNK proteins |
US20070149472A1 (en) * | 1997-08-13 | 2007-06-28 | Mckay Robert | Antisense oligonucleotide compositions and methods for the modulation of jnk proteins |
US5877309A (en) | 1997-08-13 | 1999-03-02 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotides against JNK |
US6133246A (en) * | 1997-08-13 | 2000-10-17 | Isis Pharmaceuticals Inc. | Antisense oligonucleotide compositions and methods for the modulation of JNK proteins |
US20040171564A1 (en) * | 1997-11-20 | 2004-09-02 | Honkanen Richard E. | Antisense oligonucleotide modulation of human serine/threonine protein phosphatase gene expression |
US5948902A (en) * | 1997-11-20 | 1999-09-07 | South Alabama Medical Science Foundation | Antisense oligonucleotides to human serine/threonine protein phosphatase genes |
US6673914B1 (en) | 1998-01-22 | 2004-01-06 | John Wayne Cancer Institute | Human tumor-associated gene |
US5968748A (en) * | 1998-03-26 | 1999-10-19 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of human HER-2 expression |
US20040186071A1 (en) | 1998-04-13 | 2004-09-23 | Bennett C. Frank | Antisense modulation of CD40 expression |
US7321828B2 (en) | 1998-04-13 | 2008-01-22 | Isis Pharmaceuticals, Inc. | System of components for preparing oligonucleotides |
JP2003524586A (ja) | 1998-05-21 | 2003-08-19 | 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 | オリゴヌクレオチドの非−非経口投与のための組成物と方法 |
JP2002515514A (ja) | 1998-05-21 | 2002-05-28 | 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 | オリゴヌクレオチドの局所送逹のための組成物及び方法 |
US6300319B1 (en) | 1998-06-16 | 2001-10-09 | Isis Pharmaceuticals, Inc. | Targeted oligonucleotide conjugates |
US6867294B1 (en) | 1998-07-14 | 2005-03-15 | Isis Pharmaceuticals, Inc. | Gapped oligomers having site specific chiral phosphorothioate internucleoside linkages |
US6043352A (en) | 1998-08-07 | 2000-03-28 | Isis Pharmaceuticals, Inc. | 2'-O-Dimethylaminoethyloxyethyl-modified oligonucleotides |
US6673912B1 (en) | 1998-08-07 | 2004-01-06 | Isis Pharmaceuticals, Inc. | 2′-O-aminoethyloxyethyl-modified oligonucleotides |
US20040009938A1 (en) * | 1998-08-07 | 2004-01-15 | Muthiah Manoharan | Methods of enhancing renal uptake of oligonucleotides |
US6175004B1 (en) | 1998-09-01 | 2001-01-16 | Isis Pharmaceuticals, Inc. | Process for the synthesis of oligonucleotides incorporating 2-aminoadenosine |
US6225293B1 (en) | 1998-09-02 | 2001-05-01 | Isis Pharmaceuticals, Inc. | Methods and compounds for tracking the biodistribution of macromolecule-carrier combinations |
US6077709A (en) | 1998-09-29 | 2000-06-20 | Isis Pharmaceuticals Inc. | Antisense modulation of Survivin expression |
US6069243A (en) * | 1998-10-06 | 2000-05-30 | Isis Pharmaceuticals, Inc. | Process for oligonucleotide synthesis |
US6492111B1 (en) * | 1998-11-25 | 2002-12-10 | Isis Pharmaceuticals, Inc. | In situ binary synthesis of biologically effective molecules |
US6300320B1 (en) | 1999-01-05 | 2001-10-09 | Isis Pharmaceuticals, Inc. | Modulation of c-jun using inhibitors of protein kinase C |
US6403779B1 (en) | 1999-01-08 | 2002-06-11 | Isis Pharmaceuticals, Inc. | Regioselective synthesis of 2′-O-modified nucleosides |
US6127124A (en) * | 1999-01-20 | 2000-10-03 | Isis Pharmaceuticals, Inc. | Fluorescence based nuclease assay |
US6399765B1 (en) * | 1999-03-17 | 2002-06-04 | Isis Pharmaceuticals, Inc. | Methods for removing dimethoxytrityl groups from oligonucleotides |
US6235891B1 (en) | 1999-03-31 | 2001-05-22 | South Alabama Medical Science Foundation | Glucocorticoid receptor agonist and decreased PP5 |
US7098192B2 (en) | 1999-04-08 | 2006-08-29 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of STAT3 expression |
US8541548B2 (en) * | 1999-06-07 | 2013-09-24 | Arrowhead Madison Inc. | Compounds and methods for reversible modification of biologically active molecules |
US20080281041A1 (en) | 1999-06-07 | 2008-11-13 | Rozema David B | Reversibly Masked Polymers |
US6656730B1 (en) | 1999-06-15 | 2003-12-02 | Isis Pharmaceuticals, Inc. | Oligonucleotides conjugated to protein-binding drugs |
US6147200A (en) * | 1999-08-19 | 2000-11-14 | Isis Pharmaceuticals, Inc. | 2'-O-acetamido modified monomers and oligomers |
US6277982B1 (en) | 1999-08-20 | 2001-08-21 | Isis Pharmaceuticals, Inc. | Alkylation of alcohols, amines, thiols and their derivatives by cyclic sulfate intermediates |
US7026469B2 (en) * | 2000-10-19 | 2006-04-11 | Wake Forest University School Of Medicine | Compositions and methods of double-targeting virus infections and cancer cells |
US20020055479A1 (en) | 2000-01-18 | 2002-05-09 | Cowsert Lex M. | Antisense modulation of PTP1B expression |
US6261840B1 (en) | 2000-01-18 | 2001-07-17 | Isis Pharmaceuticals, Inc. | Antisense modulation of PTP1B expression |
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 |
US8273866B2 (en) * | 2002-02-20 | 2012-09-25 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SINA) |
US20080039414A1 (en) * | 2002-02-20 | 2008-02-14 | Sima Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US20050233329A1 (en) * | 2002-02-20 | 2005-10-20 | Sirna Therapeutics, Inc. | Inhibition of gene expression using duplex forming oligonucleotides |
CA2398282A1 (en) * | 2000-02-11 | 2001-08-16 | Ribozyme Pharmaceuticals, Inc. | Method and reagent for the modulation and diagnosis of cd20 and nogo gene expression |
US20050032733A1 (en) * | 2001-05-18 | 2005-02-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (SiNA) |
US6680172B1 (en) | 2000-05-16 | 2004-01-20 | Regents Of The University Of Michigan | Treatments and markers for cancers of the central nervous system |
US7105962B2 (en) * | 2000-08-03 | 2006-09-12 | Matsushita Electric Industrial Co., Ltd. | Brushless motor for partable electronic equipment with wire treatment technique of coils |
US8568766B2 (en) | 2000-08-24 | 2013-10-29 | Gattadahalli M. Anantharamaiah | Peptides and peptide mimetics to treat pathologies associated with eye disease |
US20050209179A1 (en) * | 2000-08-30 | 2005-09-22 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA) |
US20080032942A1 (en) * | 2000-08-30 | 2008-02-07 | Mcswiggen James | RNA interference mediated treatment of Alzheimer's disease using short interfering nucleic acid (siNA) |
EP2336166A1 (en) | 2000-10-12 | 2011-06-22 | University Of Rochester | Compositions that inhibit proliferation of cancer cells |
US7309696B2 (en) | 2000-10-19 | 2007-12-18 | Wake Forest University | Compositions and methods for targeting cancer cells |
US7767802B2 (en) | 2001-01-09 | 2010-08-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of anti-apoptotic genes |
KR20020069627A (ko) * | 2001-02-27 | 2002-09-05 | 동부한농화학 주식회사 | 육환의 아자슈거를 가진 뉴클레오타이드 유도체를 포함한포스포로티오에이트 올리고뉴클레오타이드 및 이들의에이즈 치료제로서의 새로운 용도 |
JP2004537516A (ja) | 2001-05-11 | 2004-12-16 | オラセンス リミテッド | アンチセンス浸透促進剤 |
US20050079610A1 (en) * | 2001-05-18 | 2005-04-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of Fos gene expression using short interfering nucleic acid (siNA) |
US20050164966A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of type 1 insulin-like growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050222066A1 (en) * | 2001-05-18 | 2005-10-06 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20080161256A1 (en) * | 2001-05-18 | 2008-07-03 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20050182007A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050233997A1 (en) * | 2001-05-18 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of matrix metalloproteinase 13 (MMP13) gene expression using short interfering nucleic acid (siNA) |
US20050054598A1 (en) * | 2002-02-20 | 2005-03-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition hairless (HR) gene expression using short interfering nucleic acid (siNA) |
US7517864B2 (en) * | 2001-05-18 | 2009-04-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050124568A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of acetyl-CoA-carboxylase gene expression using short interfering nucleic acid (siNA) |
US20050282188A1 (en) * | 2001-05-18 | 2005-12-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20040198682A1 (en) * | 2001-11-30 | 2004-10-07 | Mcswiggen James | RNA interference mediated inhibition of placental growth factor gene expression using short interfering nucleic acid (siNA) |
US20050130181A1 (en) * | 2001-05-18 | 2005-06-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of wingless gene expression using short interfering nucleic acid (siNA) |
US20050287128A1 (en) * | 2001-05-18 | 2005-12-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TGF-beta and TGF-beta receptor gene expression using short interfering nucleic acid (siNA) |
US20050164967A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of platelet-derived endothelial cell growth factor (ECGF1) gene expression using short interfering nucleic acid (siNA) |
US20050054596A1 (en) * | 2001-11-30 | 2005-03-10 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20080188430A1 (en) * | 2001-05-18 | 2008-08-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hypoxia inducible factor 1 (HIF1) gene expression using short interfering nucleic acid (siNA) |
US20050124567A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TRPM7 gene expression using short interfering nucleic acid (siNA) |
US9994853B2 (en) | 2001-05-18 | 2018-06-12 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US20050159380A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of angiopoietin gene expression using short interfering nucleic acid (siNA) |
US20050137155A1 (en) * | 2001-05-18 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA) |
US20050187174A1 (en) * | 2001-05-18 | 2005-08-25 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of intercellular adhesion molecule (ICAM) gene expression using short interfering nucleic acid (siNA) |
US20050164224A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cyclin D1 gene expression using short interfering nucleic acid (siNA) |
US20050148530A1 (en) * | 2002-02-20 | 2005-07-07 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050159379A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc | RNA interference mediated inhibition of gastric inhibitory polypeptide (GIP) and gastric inhibitory polypeptide receptor (GIPR) gene expression using short interfering nucleic acid (siNA) |
US20060241075A1 (en) * | 2001-05-18 | 2006-10-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of desmoglein gene expression using short interfering nucleic acid (siNA) |
US20050227935A1 (en) * | 2001-05-18 | 2005-10-13 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of TNF and TNF receptor gene expression using short interfering nucleic acid (siNA) |
US20050124566A1 (en) * | 2001-05-18 | 2005-06-09 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of myostatin gene expression using short interfering nucleic acid (siNA) |
US20070042983A1 (en) * | 2001-05-18 | 2007-02-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20050153915A1 (en) * | 2001-05-18 | 2005-07-14 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of early growth response gene expression using short interfering nucleic acid (siNA) |
US20060019913A1 (en) * | 2001-05-18 | 2006-01-26 | Sirna Therapeutics, Inc. | RNA interference mediated inhibtion of protein tyrosine phosphatase-1B (PTP-1B) gene expression using short interfering nucleic acid (siNA) |
US20050182009A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of NF-Kappa B / REL-A gene expression using short interfering nucleic acid (siNA) |
US20050143333A1 (en) * | 2001-05-18 | 2005-06-30 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of interleukin and interleukin receptor gene expression using short interfering nucleic acid (SINA) |
US20050136436A1 (en) * | 2001-05-18 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of G72 and D-amino acid oxidase (DAAO) gene expression using short interfering nucleic acid (siNA) |
US20050233344A1 (en) * | 2001-05-18 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of platelet derived growth factor (PDGF) and platelet derived growth factor receptor (PDGFR) gene expression using short interfering nucleic acid (siNA) |
US20050080031A1 (en) * | 2001-05-18 | 2005-04-14 | Sirna Therapeutics, Inc. | Nucleic acid treatment of diseases or conditions related to levels of Ras, HER2 and HIV |
US20040209831A1 (en) * | 2002-02-20 | 2004-10-21 | Mcswiggen James | RNA interference mediated inhibition of hepatitis C virus (HCV) gene expression using short interfering nucleic acid (siNA) |
US20050203040A1 (en) * | 2001-05-18 | 2005-09-15 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of vascular cell adhesion molecule (VCAM) gene expression using short interfering nucleic acid (siNA) |
US20050176666A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of GPRA and AAA1 gene expression using short interfering nucleic acid (siNA) |
US20040219671A1 (en) * | 2002-02-20 | 2004-11-04 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of parkinson disease using short interfering nucleic acid (siNA) |
US20060142226A1 (en) * | 2001-05-18 | 2006-06-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cholesteryl ester transfer protein (CETP) gene expression using short interfering nucleic acid (siNA) |
US20050209180A1 (en) * | 2001-05-18 | 2005-09-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hepatitis C virus (HCV) expression using short interfering nucleic acid (siNA) |
US20050233996A1 (en) * | 2002-02-20 | 2005-10-20 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA) |
US20050196767A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of GRB2 associated binding protein (GAB2) gene expression using short interfering nucleic acis (siNA) |
US20050119212A1 (en) * | 2001-05-18 | 2005-06-02 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of FAS and FASL gene expression using short interfering nucleic acid (siNA) |
US20050014172A1 (en) * | 2002-02-20 | 2005-01-20 | Ivan Richards | RNA interference mediated inhibition of muscarinic cholinergic receptor gene expression using short interfering nucleic acid (siNA) |
US20050196765A1 (en) * | 2001-05-18 | 2005-09-08 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of checkpoint Kinase-1 (CHK-1) gene expression using short interfering nucleic acid (siNA) |
US20050119211A1 (en) * | 2001-05-18 | 2005-06-02 | Sirna Therapeutics, Inc. | RNA mediated inhibition connexin gene expression using short interfering nucleic acid (siNA) |
US20050256068A1 (en) * | 2001-05-18 | 2005-11-17 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of stearoyl-CoA desaturase (SCD) gene expression using short interfering nucleic acid (siNA) |
US20050191638A1 (en) * | 2002-02-20 | 2005-09-01 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
US20070270579A1 (en) * | 2001-05-18 | 2007-11-22 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acid (siNA) |
US20050159382A1 (en) * | 2001-05-18 | 2005-07-21 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of polycomb group protein EZH2 gene expression using short interfering nucleic acid (siNA) |
US20050164968A1 (en) * | 2001-05-18 | 2005-07-28 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of ADAM33 gene expression using short interfering nucleic acid (siNA) |
US20050176665A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of hairless (HR) gene expression using short interfering nucleic acid (siNA) |
US20060142225A1 (en) * | 2001-05-18 | 2006-06-29 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cyclin dependent kinase-2 (CDK2) gene expression using short interfering nucleic acid (siNA) |
US20050176664A1 (en) * | 2001-05-18 | 2005-08-11 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of cholinergic muscarinic receptor (CHRM3) gene expression using short interfering nucleic acid (siNA) |
US20050182006A1 (en) * | 2001-05-18 | 2005-08-18 | Sirna Therapeutics, Inc | RNA interference mediated inhibition of protein kinase C alpha (PKC-alpha) gene expression using short interfering nucleic acid (siNA) |
US20050159376A1 (en) * | 2002-02-20 | 2005-07-21 | Slrna Therapeutics, Inc. | RNA interference mediated inhibition 5-alpha reductase and androgen receptor gene expression using short interfering nucleic acid (siNA) |
US6960738B2 (en) * | 2001-05-29 | 2005-11-01 | Koninklijke Philips Electronics N.V. | Metal-ceramic bond |
US7803915B2 (en) | 2001-06-20 | 2010-09-28 | Genentech, Inc. | Antibody compositions for the diagnosis and treatment of tumor |
KR100607612B1 (ko) | 2001-06-20 | 2006-08-02 | 제넨테크, 인크. | 종양의 진단 및 치료를 위한 방법 및 이를 위한 조성물 |
WO2003000707A2 (en) | 2001-06-21 | 2003-01-03 | Isis Pharmaceuticals, Inc. | Antisense modulation of superoxide dismutase 1, soluble expression |
US7425545B2 (en) | 2001-07-25 | 2008-09-16 | Isis Pharmaceuticals, Inc. | Modulation of C-reactive protein expression |
US6964950B2 (en) | 2001-07-25 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of C-reactive protein expression |
US20030096772A1 (en) | 2001-07-30 | 2003-05-22 | Crooke Rosanne M. | Antisense modulation of acyl CoA cholesterol acyltransferase-2 expression |
US7407943B2 (en) | 2001-08-01 | 2008-08-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein B expression |
US7227014B2 (en) | 2001-08-07 | 2007-06-05 | Isis Pharmaceuticals, Inc. | Antisense modulation of apolipoprotein (a) expression |
JP4714413B2 (ja) * | 2001-08-31 | 2011-06-29 | トムソン ライセンシング | オーディオビジュアルストリームのためのシーケンスカウンタ |
EP2153843B1 (en) | 2001-09-18 | 2012-08-15 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
NZ585001A (en) | 2001-10-09 | 2011-08-26 | Isis Pharmaceuticals Inc | Antisense modulation of insulin-like growth factor binding protein 5 expression |
US6750019B2 (en) | 2001-10-09 | 2004-06-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of insulin-like growth factor binding protein 5 expression |
US20040138163A1 (en) * | 2002-05-29 | 2004-07-15 | Mcswiggen James | RNA interference mediated inhibition of vascular edothelial growth factor and vascular edothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20070203333A1 (en) * | 2001-11-30 | 2007-08-30 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US20050075304A1 (en) * | 2001-11-30 | 2005-04-07 | Mcswiggen James | RNA interference mediated inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor gene expression using short interfering nucleic acid (siNA) |
US6965025B2 (en) | 2001-12-10 | 2005-11-15 | Isis Pharmaceuticals, Inc. | Antisense modulation of connective tissue growth factor expression |
US20030228305A1 (en) | 2002-01-02 | 2003-12-11 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US9657294B2 (en) | 2002-02-20 | 2017-05-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US9181551B2 (en) | 2002-02-20 | 2015-11-10 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
US20050137153A1 (en) * | 2002-02-20 | 2005-06-23 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of alpha-1 antitrypsin (AAT) gene expression using short interfering nucleic acid (siNA) |
US20050096284A1 (en) * | 2002-02-20 | 2005-05-05 | Sirna Therapeutics, Inc. | RNA interference mediated treatment of polyglutamine (polyQ) repeat expansion diseases using short interfering nucleic acid (siNA) |
US20050222064A1 (en) * | 2002-02-20 | 2005-10-06 | Sirna Therapeutics, Inc. | Polycationic compositions for cellular delivery of polynucleotides |
US20030191075A1 (en) * | 2002-02-22 | 2003-10-09 | Cook Phillip Dan | Method of using modified oligonucleotides for hepatic delivery |
US8138383B2 (en) * | 2002-03-11 | 2012-03-20 | Arrowhead Madison Inc. | Membrane active heteropolymers |
US8008355B2 (en) * | 2002-03-11 | 2011-08-30 | Roche Madison Inc. | Endosomolytic poly(vinyl ether) polymers |
US20030180712A1 (en) | 2002-03-20 | 2003-09-25 | Biostratum Ab | Inhibition of the beta3 subunit of L-type Ca2+ channels |
US7169916B2 (en) * | 2002-04-01 | 2007-01-30 | Isis Pharmaceuticals, Inc. | Chloral-free DCA in oligonucleotide synthesis |
EP1571968A4 (en) | 2002-04-16 | 2007-10-17 | Genentech Inc | COMPOSITIONS AND METHODS FOR DIAGNOSIS AND TREATMENT OF TUMORS |
US7199107B2 (en) | 2002-05-23 | 2007-04-03 | Isis Pharmaceuticals, Inc. | Antisense modulation of kinesin-like 1 expression |
CA2488048A1 (en) | 2002-05-30 | 2003-12-11 | Memorial Sloan-Kettering Cancer Center | Kinase suppressor of ras inactivation for therapy of ras mediated tumorigenesis |
WO2003105780A2 (en) * | 2002-06-18 | 2003-12-24 | Epigenesis Pharmaceuticals, Inc. | A dry powder oligonucleotide formulation, preparation and its uses |
US20040019000A1 (en) * | 2002-07-19 | 2004-01-29 | Muthiah Manoharan | Polyalkyleneamine-containing oligomers |
AU2003257285A1 (en) * | 2002-07-25 | 2004-02-16 | Micrologix Biotech Inc. | Inhibitors of rna dependent rna polymerase and uses thereof |
EP1575992A4 (en) | 2002-08-05 | 2007-02-21 | Univ Rochester | CHIMERIC PROTEINS WITH PROTEIN TRANSDUCTION FIELD / DOMAINE DESAMINASE, ASSOCIATED COMPOUNDS AND CORRESPONDING USES |
US6878805B2 (en) * | 2002-08-16 | 2005-04-12 | Isis Pharmaceuticals, Inc. | Peptide-conjugated oligomeric compounds |
US7923547B2 (en) | 2002-09-05 | 2011-04-12 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA) |
BR0314236A (pt) | 2002-09-13 | 2005-08-09 | Replicor Inc | Formulação de oligonucleotìdeo, composição farmacêutica, kit, composto antiviral, preparação de oligonucleotìdeo e métodos para seleção de um oligonucleotìdeo antiviral para uso como um agente antiviral, para profilaxia ou tratamento de uma infecção viral em um paciente, para tratamento profilático de câncer causado por oncovìrus, para identificação de um composto que altera a ligação de um oligonucleotìdeo a pelo menos um componente viral, para purificação da ligação de oligonucleotìdeos a pelo menos um componente viral e para enriquecimento de oligonucleotìdeos a partir de um agrupamento de oligonucleotìdeos |
WO2004027030A2 (en) * | 2002-09-18 | 2004-04-01 | Isis Pharmaceuticals, Inc. | Efficient reduction of target rna’s by single- and double-stranded oligomeric compounds |
EP2272958A1 (en) | 2002-09-26 | 2011-01-12 | ISIS Pharmaceuticals, Inc. | Modulation of forkhead box O1A expression |
AU2003287505A1 (en) | 2002-11-05 | 2004-06-03 | Isis Pharmaceuticals, Inc. | Chimeric oligomeric compounds and their use in gene modulation |
US9150606B2 (en) | 2002-11-05 | 2015-10-06 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2'-modified nucleosides for use in gene modulation |
AU2003291753B2 (en) | 2002-11-05 | 2010-07-08 | Isis Pharmaceuticals, Inc. | Polycyclic sugar surrogate-containing oligomeric compounds and compositions for use in gene modulation |
AU2003291755A1 (en) | 2002-11-05 | 2004-06-07 | Isis Pharmaceuticals, Inc. | Oligomers comprising modified bases for binding cytosine and uracil or thymine and their use |
US9150605B2 (en) | 2002-11-05 | 2015-10-06 | Isis Pharmaceuticals, Inc. | Compositions comprising alternating 2′-modified nucleosides for use in gene modulation |
PT2336318E (pt) | 2002-11-13 | 2013-06-12 | Genzyme Corp | Modulação anti-sentido da expressão de apolipoproteína b |
EP1569695B1 (en) | 2002-11-13 | 2013-05-15 | Genzyme Corporation | Antisense modulation of apolipoprotein b expression |
EP1572971B1 (en) | 2002-11-15 | 2009-09-30 | Morphotek Inc. | Methods of generating high-production of antibodies from hybridomas created by in vitro immunization |
AU2003298650B2 (en) | 2002-11-15 | 2010-03-11 | Musc Foundation For Research Development | Complement receptor 2 targeted complement modulators |
CA2507044A1 (en) | 2002-11-21 | 2004-06-10 | Mary Lucero | Purinergic modulation of smell |
US7144999B2 (en) | 2002-11-23 | 2006-12-05 | Isis Pharmaceuticals, Inc. | Modulation of hypoxia-inducible factor 1 alpha expression |
US20040231231A1 (en) * | 2002-12-20 | 2004-11-25 | Cataldo Dominic A. | Use of colloidal clays for sustained release of active ingredients |
NZ541637A (en) | 2003-02-11 | 2008-07-31 | Antisense Therapeutics Pty Ltd | Modulation of insulin like growth factor I receptor |
US7002006B2 (en) * | 2003-02-12 | 2006-02-21 | Isis Pharmaceuticals, Inc. | Protection of nucleosides |
US7803781B2 (en) | 2003-02-28 | 2010-09-28 | Isis Pharmaceuticals, Inc. | Modulation of growth hormone receptor expression and insulin-like growth factor expression |
WO2004090108A2 (en) * | 2003-04-03 | 2004-10-21 | Alnylam Pharmaceuticals | Irna conjugates |
US20040185559A1 (en) | 2003-03-21 | 2004-09-23 | Isis Pharmaceuticals Inc. | Modulation of diacylglycerol acyltransferase 1 expression |
US20040198640A1 (en) * | 2003-04-02 | 2004-10-07 | Dharmacon, Inc. | Stabilized polynucleotides for use in RNA interference |
US7598227B2 (en) | 2003-04-16 | 2009-10-06 | Isis Pharmaceuticals Inc. | Modulation of apolipoprotein C-III expression |
US7399853B2 (en) | 2003-04-28 | 2008-07-15 | Isis Pharmaceuticals | Modulation of glucagon receptor expression |
US7897582B2 (en) * | 2003-05-23 | 2011-03-01 | Isis Pharmaceuticals, Inc. | Oligonucleotide compositions and methods for the modulation of the expression of B7 protein |
US7960355B2 (en) * | 2003-05-23 | 2011-06-14 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of the expression of B7 protein |
US7276599B2 (en) | 2003-06-02 | 2007-10-02 | Isis Pharmaceuticals, Inc. | Oligonucleotide synthesis with alternative solvents |
CA2524495A1 (en) | 2003-06-03 | 2005-01-13 | Eli Lilly And Company | Modulation of survivin expression |
DK3604537T3 (da) | 2003-06-13 | 2022-02-28 | Alnylam Europe Ag | Dobbeltstrenget ribonukleinsyre med forøget effektivitet i en organisme |
EP1644475A4 (en) * | 2003-06-20 | 2009-06-03 | Isis Pharmaceuticals Inc | DOUBLE-STRAND COMPOSITIONS WITH A 3'-ENDO-MODIFIED STRING FOR USE IN GENE MODULATION |
EP1648914A4 (en) | 2003-07-31 | 2009-12-16 | Regulus Therapeutics Inc | OLIGOMERIC COMPOUNDS AND COMPOSITIONS USEFUL FOR MODULATING SMALL NON-CODING RNA |
US7825235B2 (en) | 2003-08-18 | 2010-11-02 | Isis Pharmaceuticals, Inc. | Modulation of diacylglycerol acyltransferase 2 expression |
US20050053981A1 (en) | 2003-09-09 | 2005-03-10 | Swayze Eric E. | Gapped oligomeric compounds having linked bicyclic sugar moieties at the termini |
AU2004274021B2 (en) | 2003-09-18 | 2009-08-13 | Isis Pharmaceuticals, Inc. | 4'-thionucleosides and oligomeric compounds |
PE20050469A1 (es) | 2003-09-18 | 2005-09-10 | Lilly Co Eli | Modulacion de la expresion de eif4e |
US7125945B2 (en) * | 2003-09-19 | 2006-10-24 | Varian, Inc. | Functionalized polymer for oligonucleotide purification |
PT1678194E (pt) | 2003-10-10 | 2013-09-30 | Alchemia Oncology Pty Ltd | Modulação da síntese e degradação de hialuronano no tratamento de doença |
US20050191653A1 (en) | 2003-11-03 | 2005-09-01 | Freier Susan M. | Modulation of SGLT2 expression |
SI2161283T1 (sl) | 2003-11-17 | 2014-10-30 | Genentech, Inc. | Sestavki, ki obsegajo protitelesa proti CD79b, konjugirana na sredstvo, ki inhibira rast, ali na citotoksično sredstvo, in postopki za zdravljenje tumorja hematopoetskega izvora |
JP2007520222A (ja) | 2004-01-20 | 2007-07-26 | アイシス ファーマシューティカルズ インコーポレイテッド | グルココルチコイドレセプター発現の調節 |
US8778900B2 (en) * | 2004-01-22 | 2014-07-15 | Isis Pharmaceuticals, Inc. | Modulation of eIF4E-BP1 expression |
US7468431B2 (en) | 2004-01-22 | 2008-12-23 | Isis Pharmaceuticals, Inc. | Modulation of eIF4E-BP2 expression |
US20050187191A1 (en) * | 2004-02-20 | 2005-08-25 | Kucera Louis S. | Methods and compositions for the treatment of respiratory syncytial virus |
US8569474B2 (en) | 2004-03-09 | 2013-10-29 | Isis Pharmaceuticals, Inc. | Double stranded constructs comprising one or more short strands hybridized to a longer strand |
EP2700720A3 (en) | 2004-03-15 | 2015-01-28 | Isis Pharmaceuticals, Inc. | Compositions and methods for optimizing cleavage of RNA by RNASE H |
KR101147147B1 (ko) * | 2004-04-01 | 2012-05-25 | 머크 샤프 앤드 돔 코포레이션 | Rna 간섭의 오프 타겟 효과 감소를 위한 변형된폴리뉴클레오타이드 |
AU2005230684B2 (en) | 2004-04-05 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Process and reagents for oligonucleotide synthesis and purification |
US20050244869A1 (en) | 2004-04-05 | 2005-11-03 | Brown-Driver Vickie L | Modulation of transthyretin expression |
EP1750776A2 (en) | 2004-04-30 | 2007-02-14 | Alnylam Pharmaceuticals Inc. | Oligonucleotides comprising a c5-modified pyrimidine |
US8039588B2 (en) | 2004-05-21 | 2011-10-18 | The Uab Research Foundation | Variable lymphocyte receptors |
US10508277B2 (en) | 2004-05-24 | 2019-12-17 | Sirna Therapeutics, Inc. | Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference |
US8394947B2 (en) | 2004-06-03 | 2013-03-12 | Isis Pharmaceuticals, Inc. | Positionally modified siRNA constructs |
US20090048192A1 (en) * | 2004-06-03 | 2009-02-19 | Isis Pharmaceuticals, Inc. | Double Strand Compositions Comprising Differentially Modified Strands for Use in Gene Modulation |
ATE498685T1 (de) | 2004-06-28 | 2011-03-15 | Univ Western Australia | Antisense-oligonukleotide zur induktion von exon- skipping sowie verfahren zur verwendung davon |
US7427675B2 (en) * | 2004-08-23 | 2008-09-23 | Isis Pharmaceuticals, Inc. | Compounds and methods for the characterization of oligonucleotides |
US7884086B2 (en) | 2004-09-08 | 2011-02-08 | Isis Pharmaceuticals, Inc. | Conjugates for use in hepatocyte free uptake assays |
EP1809303B1 (en) * | 2004-09-23 | 2019-03-06 | ARC Medical Devices, Inc. | Pharmaceutical compositions and methods relating to inhibiting fibrous adhesions or inflammatory disease using low sulphate fucans |
US7923206B2 (en) | 2004-11-22 | 2011-04-12 | Dharmacon, Inc. | Method of determining a cellular response to a biological agent |
US7923207B2 (en) | 2004-11-22 | 2011-04-12 | Dharmacon, Inc. | Apparatus and system having dry gene silencing pools |
US7935811B2 (en) | 2004-11-22 | 2011-05-03 | Dharmacon, Inc. | Apparatus and system having dry gene silencing compositions |
US9944713B2 (en) | 2004-11-24 | 2018-04-17 | Medicinal Bioconvergence Research Center | Antibody specific to the AIMP2-DX2 |
CA2620626C (en) | 2004-12-20 | 2011-06-07 | Isu Abxis Co., Ltd. | Molecules inhibiting intercellular adhesion |
CA2595407A1 (en) | 2005-01-20 | 2006-07-27 | University Of Rochester | Thioredoxin interacting protein (txnip) as regulator of vascular function |
US8067175B2 (en) | 2005-02-11 | 2011-11-29 | Memorial Sloan-Kettering Cancer Center | Methods and compositions for detecting a drug resistant EGFR mutant |
EP2050763A3 (en) | 2005-03-10 | 2009-07-15 | Genentech, Inc. | Methods and compositions for modulating vascular integrity |
US7476733B2 (en) | 2005-03-25 | 2009-01-13 | The United States Of America As Represented By The Department Of Health And Human Services | Development of a real-time PCR assay for detection of pneumococcal DNA and diagnosis of pneumococccal disease |
US9505867B2 (en) | 2005-05-31 | 2016-11-29 | Ecole Polytechmique Fédérale De Lausanne | Triblock copolymers for cytoplasmic delivery of gene-based drugs |
US8252756B2 (en) | 2005-06-14 | 2012-08-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
US8067571B2 (en) | 2005-07-13 | 2011-11-29 | Avi Biopharma, Inc. | Antibacterial antisense oligonucleotide and method |
US20090176725A1 (en) * | 2005-08-17 | 2009-07-09 | Sirna Therapeutics Inc. | Chemically modified short interfering nucleic acid molecules that mediate rna interference |
US8080534B2 (en) | 2005-10-14 | 2011-12-20 | Phigenix, Inc | Targeting PAX2 for the treatment of breast cancer |
EP2189522A1 (en) | 2005-10-14 | 2010-05-26 | MUSC Foundation For Research Development | Targeting PAX2 for the induction of DEFB1-mediated tumor immunity and cancer therapy |
AU2006305886C1 (en) * | 2005-10-28 | 2011-03-17 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of huntingtin gene |
AU2006311730B2 (en) | 2005-11-09 | 2010-12-02 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Factor V Leiden mutant gene |
WO2007062380A2 (en) | 2005-11-21 | 2007-05-31 | Isis Pharmaceuticals, Inc. | Modulation of eif4e-bp2 expression |
WO2007087113A2 (en) | 2005-12-28 | 2007-08-02 | The Scripps Research Institute | Natural antisense and non-coding rna transcripts as drug targets |
WO2008005479A2 (en) * | 2006-07-06 | 2008-01-10 | University Of Wyoming | Charge reversible polymers |
EP2008274B1 (en) | 2006-03-31 | 2015-05-27 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibiting expression of eg5 gene |
CN101437943A (zh) | 2006-05-03 | 2009-05-20 | 波罗的科技发展有限公司 | 牢固结合的碱基-修饰的寡核苷酸和人工核酸酶组合的反义药剂 |
CN101484588B (zh) | 2006-05-11 | 2013-11-06 | 阿尔尼拉姆医药品有限公司 | 抑制pcsk9基因表达的组合物和方法 |
US7812150B2 (en) | 2006-05-19 | 2010-10-12 | Alnylam Pharmaceuticals, Inc. | RNAi modulation of Aha and therapeutic uses thereof |
EP2018443A4 (en) | 2006-05-22 | 2009-11-11 | Alnylam Pharmaceuticals Inc | COMPOSITIONS AND METHODS INHIBITING EXPRESSION OF IKK-B GENE |
US20090280188A1 (en) * | 2006-06-23 | 2009-11-12 | Northwestern University | Asymmetric functionalizated nanoparticles and methods of use |
WO2008011473A2 (en) | 2006-07-19 | 2008-01-24 | Isis Pharmaceuticals, Inc. | Compositions and their uses directed to hbxip |
AU2007281082A1 (en) * | 2006-08-04 | 2008-02-07 | Isis Pharmaceuticals, Inc. | Compositions and methods for the modulation of JNK proteins |
EP2061443A4 (en) * | 2006-08-18 | 2013-07-24 | Arrowhead Res Corp | POLYCONJUGATE FOR IN VIVO ADMINISTRATION OF POLYNUCLEOTIDES |
AU2007299629C1 (en) | 2006-09-21 | 2012-05-10 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the HAMP gene |
US8252755B2 (en) | 2006-09-22 | 2012-08-28 | Dharmacon, Inc. | Duplex oligonucleotide complexes and methods for gene silencing by RNA interference |
DK2068886T3 (da) | 2006-10-03 | 2013-11-18 | Tekmira Pharmaceuticals Corp | Lipidholdige præparater |
EP2104516B1 (en) | 2006-11-01 | 2015-01-07 | University of Rochester | Methods and compositions related to the structure and function of apobec3g |
EP2104509A4 (en) | 2006-12-11 | 2010-03-24 | Univ Utah Res Found | COMPOSITIONS AND METHODS FOR TREATMENT OF PATHOLOGICAL ANGIOGENESIS AND VASCULAR PERMEABILITY |
US7947447B2 (en) | 2007-01-16 | 2011-05-24 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
MX2009008470A (es) | 2007-02-09 | 2009-11-26 | Univ Northwestern | Particulas para detectar objetivos intracelulares. |
PE20090064A1 (es) | 2007-03-26 | 2009-03-02 | Novartis Ag | Acido ribonucleico de doble cadena para inhibir la expresion del gen e6ap humano y composicion farmaceutica que lo comprende |
EP2905336A1 (en) | 2007-03-29 | 2015-08-12 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibiting expression of a gene from the ebola |
WO2008131129A2 (en) * | 2007-04-17 | 2008-10-30 | Baxter International Inc. | Nucleic acid microparticles for pulmonary delivery |
EP2826863B1 (en) | 2007-05-30 | 2017-08-23 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
EP2316943B1 (en) | 2007-07-05 | 2013-06-19 | Novartis AG | DSRNA for treating viral infection |
US8404830B2 (en) * | 2007-07-17 | 2013-03-26 | Somalogic, Inc. | Method for generating aptamers with improved off-rates |
CA2697957A1 (en) | 2007-08-28 | 2009-03-12 | Uab Research Foundation | Synthetic apolipoprotein e mimicking polypeptides and methods of use |
DK2195331T3 (da) | 2007-08-28 | 2014-02-03 | Uab Research Foundation | Syntetiske polypeptider, der efterligner apolipoprotein e, og anvendelsesmetoder |
WO2009039466A1 (en) | 2007-09-20 | 2009-03-26 | Vanderbilt University | Free solution measurement of molecular interactions by backscattering interferometry |
US7951785B2 (en) | 2007-09-21 | 2011-05-31 | California Institute Of Technology | NFIA in glial fate determination, glioma therapy and astrocytoma treatment |
MX2010003465A (es) | 2007-10-02 | 2010-07-05 | Amgen Inc | Incremento de eritropoyetina utilizando acidos nucleicos que hibridan para micro-arn y precursores de los mismos. |
US8916531B2 (en) | 2007-11-20 | 2014-12-23 | Isis Pharmaceuticals, Inc. | Modulation of CD40 expression |
AU2008335202A1 (en) | 2007-12-10 | 2009-06-18 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of Factor VII gene |
US7845686B2 (en) * | 2007-12-17 | 2010-12-07 | S & B Technical Products, Inc. | Restrained pipe joining system for plastic pipe |
US8188060B2 (en) | 2008-02-11 | 2012-05-29 | Dharmacon, Inc. | Duplex oligonucleotides with enhanced functionality in gene regulation |
CN102014932B (zh) | 2008-03-05 | 2015-11-25 | 阿尔尼拉姆医药品有限公司 | 用于抑制Eg5和VEGF基因表达的组合物和方法 |
EP2105145A1 (en) * | 2008-03-27 | 2009-09-30 | ETH Zürich | Method for muscle-specific delivery lipid-conjugated oligonucleotides |
WO2009124295A2 (en) * | 2008-04-04 | 2009-10-08 | Isis Pharmaceuticals, Inc. | Oligomeric compounds comprising bicyclic nucleosides and having reduced toxicity |
AU2009234266B2 (en) | 2008-04-11 | 2015-08-06 | Tekmira Pharmaceuticals Corporation | Site-specific delivery of nucleic acids by combining targeting ligands with endosomolytic components |
US8324366B2 (en) | 2008-04-29 | 2012-12-04 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for delivering RNAI using lipoproteins |
US20110262485A1 (en) | 2008-08-04 | 2011-10-27 | University Of Miami | Sting (stimulator of interferon genes), a regulator of innate immune responses |
EP3081648A1 (en) | 2008-08-25 | 2016-10-19 | Excaliard Pharmaceuticals, Inc. | Antisense oligonucleotides directed against connective tissue growth factor and uses thereof |
EP2690175B1 (en) | 2008-09-02 | 2016-12-28 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for combined inhibition of mutant EGFR gene and IL-6 expression |
WO2010039548A2 (en) | 2008-09-23 | 2010-04-08 | Alnylam Pharmaceuticals, Inc. | Chemical modifications of monomers and oligonucleotides with cycloaddition |
EP2334793B1 (en) | 2008-09-25 | 2016-04-06 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of serum amyloid a gene |
ES2727549T3 (es) | 2008-10-03 | 2019-10-17 | Curna Inc | Tratamiento de las enfermedades relacionadas con la apolipoproteína a1 por inhibición del transcrito antisentido natural a la apolipoproteína a1 |
CA3018487A1 (en) | 2008-10-20 | 2010-04-29 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of transthyretin |
CN102203253B (zh) | 2008-10-24 | 2016-04-06 | 萨雷普塔治疗公司 | 用于dmd的多外显子跳跃组合物 |
EP2358398A2 (en) | 2008-10-24 | 2011-08-24 | Isis Pharmaceuticals, Inc. | Oligomeric compounds and methods |
CA3039251C (en) | 2008-11-10 | 2024-01-09 | Arbutus Biopharma Corporation | Novel lipids and compositions for the delivery of therapeutics |
WO2010060110A1 (en) | 2008-11-24 | 2010-05-27 | Northwestern University | Polyvalent rna-nanoparticle compositions |
RU2015151857A (ru) | 2008-12-02 | 2019-01-15 | Уэйв Лайф Сайенсес Джапан, Инк. | Способ синтеза модифицированных по атому фосфора нуклеиновых кислот |
ES2600781T3 (es) | 2008-12-04 | 2017-02-10 | Curna, Inc. | Tratamiento para enfermedades relacionadas con el factor de crecimiento del endotelio vascular (vegf) mediante la inhibición de transcritos antisentido naturales de vegf |
RU2551234C2 (ru) | 2008-12-04 | 2015-05-20 | КьюРНА,Инк.,US | Лечение сиртуин 1 (sirt1)-связанных заболеваний путем ингибирования натурального антисмыслового транскрипта |
JP5923306B2 (ja) | 2008-12-04 | 2016-05-24 | クルナ・インコーポレーテッド | 腫瘍抑制遺伝子に対する天然アンチセンス転写物の抑制による腫瘍抑制遺伝子関連疾患の治療 |
KR101829469B1 (ko) | 2008-12-04 | 2018-03-30 | 큐알엔에이, 인크. | Epo에 대한 천연 안티센스 전사체의 억제에 의해 에리트로포에틴(epo) 관련된 질환의 치료 |
CA2746514C (en) | 2008-12-10 | 2018-11-27 | Alnylam Pharmaceuticals, Inc. | Gnaq targeted dsrna compositions and methods for inhibiting expression |
US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
US20120021515A1 (en) | 2009-02-06 | 2012-01-26 | Swayze Eric E | Oligomeric compounds and methods |
ES2658626T3 (es) | 2009-02-12 | 2018-03-12 | Curna, Inc. | Tratamiento de enfermedades relacionadas con el factor neurotrófico derivado de células gliales (GDNF) por inhibición de transcrito antisentido natural a GDNF |
WO2010093904A2 (en) | 2009-02-12 | 2010-08-19 | Curna, Inc. | Treatment of brain derived neurotrophic factor (bdnf) related diseases by inhibition of natural antisense transcript to bdnf |
WO2010099341A1 (en) | 2009-02-26 | 2010-09-02 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of mig-12 gene |
WO2010101951A1 (en) | 2009-03-02 | 2010-09-10 | Alnylam Pharmaceuticals, Inc. | Nucleic acid chemical modifications |
EP2963116B1 (en) | 2009-03-04 | 2020-11-11 | CuRNA, Inc. | Treatment of sirtuin 1 (sirt1) related diseases by inhibition of natural antisense transcript to sirt 1 |
WO2010105209A1 (en) | 2009-03-12 | 2010-09-16 | Alnylam Pharmaceuticals, Inc. | LIPID FORMULATED COMPOSITIONS AND METHODS FOR INHIBITING EXPRESSION OF Eg5 AND VEGF GENES |
EP2408919B1 (en) | 2009-03-16 | 2017-10-18 | CuRNA, Inc. | Treatment of nuclear factor (erythroid-derived 2)-like 2 (nrf2) related diseases by inhibition of natural antisense transcript to nrf2 |
ES2627763T3 (es) | 2009-03-17 | 2017-07-31 | Curna, Inc. | Tratamiento de enfermedades relacionadas con el homólogo tipo delta 1 (dlk1) por inhibición de transcrito antisentido natural a dlk1 |
US20120035247A1 (en) | 2009-03-19 | 2012-02-09 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 6 (STAT6) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
JP2012520685A (ja) | 2009-03-19 | 2012-09-10 | メルク・シャープ・エンド・ドーム・コーポレイション | 低分子干渉核酸(siNA)を用いたGATA結合タンパク質3(GATA3)遺伝子発現のRNA干渉媒介性阻害 |
CA2755773A1 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | Rna interference mediated inhibition of btb and cnc homology 1, basic leucine zipper transcription factor 1 (bach 1) gene expression using short interfering nucleic acid (sina) |
US20120016011A1 (en) | 2009-03-19 | 2012-01-19 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Connective Tissue Growth Factor (CTGF) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
EP2411516A1 (en) | 2009-03-27 | 2012-02-01 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF APOPTOSIS SIGNAL-REGULATING KINASE 1 (ASK1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
WO2010111497A2 (en) | 2009-03-27 | 2010-09-30 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF THE INTERCELLULAR ADHESION MOLECULE 1 (ICAM-1)GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
US20120022142A1 (en) | 2009-03-27 | 2012-01-26 | Merck Sharp & Dohme Corp. | RNA Interference Mediated Inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
US20120004281A1 (en) | 2009-03-27 | 2012-01-05 | Merck Sharp & Dohme Corp | RNA Interference Mediated Inhibition of the Nerve Growth Factor Beta Chain (NGFB) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
US20120022143A1 (en) | 2009-03-27 | 2012-01-26 | Merck Sharp & Dohme Corp | RNA Interference Mediated Inhibition of the Thymic Stromal Lymphopoietin (TSLP) Gene Expression Using Short Interfering Nucliec Acid (siNA) |
EP3524275A1 (en) | 2009-04-22 | 2019-08-14 | Massachusetts Institute Of Technology | Innate immune supression enables repeated delivery of long rna molecules |
DK2424987T3 (en) | 2009-05-01 | 2018-02-26 | Curna Inc | TREATMENT OF HEMOGLOBIN (HBF / HBG) RELATED DISEASES BY INHIBITION OF NATURAL ANTISENSE TRANSCRIPTION TO HBF / HBG |
JP6250930B2 (ja) | 2009-05-06 | 2017-12-20 | クルナ・インコーポレーテッド | トリステトラプロリン(ttp)に対する天然アンチセンス転写物の抑制によるttp関連疾患の治療 |
CN102459596B (zh) | 2009-05-06 | 2016-09-07 | 库尔纳公司 | 通过针对脂质转运和代谢基因的天然反义转录物的抑制治疗脂质转运和代谢基因相关疾病 |
EP2427554B1 (en) | 2009-05-08 | 2016-11-16 | CuRNA, Inc. | Treatment of dystrophin family related diseases by inhibition of natural antisense transcript to dmd family |
CN102575251B (zh) | 2009-05-18 | 2018-12-04 | 库尔纳公司 | 通过抑制针对重编程因子的天然反义转录物来治疗重编程因子相关的疾病 |
JP2012527248A (ja) | 2009-05-22 | 2012-11-08 | クルナ・インコーポレーテッド | 転写因子e3(tfe3)に対する天然アンチセンス転写物の阻害によるtfe3およびインスリン受容体基質2(irs2)関連疾患の処置 |
KR101704988B1 (ko) | 2009-05-28 | 2017-02-08 | 큐알엔에이, 인크. | 항바이러스 유전자에 대한 천연 안티센스 전사체의 억제에 의한 항바이러스 유전자 관련된 질환의 치료 |
LT2440183T (lt) | 2009-06-10 | 2018-08-10 | Arbutus Biopharma Corporation | Patobulinta lipido kompozicija |
CA2765509C (en) | 2009-06-16 | 2021-08-17 | Joseph Collard | Treatment of paraoxonase 1 (pon1) related diseases by inhibition of natural antisense transcript to pon1 |
WO2010148050A2 (en) | 2009-06-16 | 2010-12-23 | Curna, Inc. | Treatment of collagen gene related diseases by inhibition of natural antisense transcript to a collagen gene |
HUE046966T2 (hu) | 2009-06-17 | 2020-04-28 | Biogen Ma Inc | Készítmények és módszerek az SMN2 splicing egy alanynál történõ modulálására |
KR101807323B1 (ko) | 2009-06-24 | 2017-12-08 | 큐알엔에이, 인크. | Tnfr2에 대한 천연 안티센스 전사체의 억제에 의한 종양 괴사 인자 수용체 2(tnfr2) 관련된 질환의 치료 |
CA2765815A1 (en) | 2009-06-26 | 2010-12-29 | Opko Curna, Llc | Treatment of down syndrome gene related diseases by inhibition of natural antisense transcript to a down syndrome gene |
AU2010270714B2 (en) | 2009-07-06 | 2015-08-13 | Wave Life Sciences Ltd. | Novel nucleic acid prodrugs and methods use thereof |
WO2011005860A2 (en) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | 5' phosphate mimics |
WO2011005861A1 (en) | 2009-07-07 | 2011-01-13 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide end caps |
CA2768947C (en) | 2009-07-24 | 2018-06-19 | Opko Curna, Llc | Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) |
EP2462229B1 (en) | 2009-08-05 | 2016-05-11 | CuRNA, Inc. | Treatment of insulin gene (ins) related diseases by inhibition of natural antisense transcript to an insulin gene (ins) |
CN102625841A (zh) | 2009-08-11 | 2012-08-01 | 欧科库尔纳有限责任公司 | 通过抑制脂连蛋白(adipoq)的天然反义转录物治疗脂连蛋白(adipoq)相关疾病 |
EP2464336A4 (en) | 2009-08-14 | 2013-11-20 | Alnylam Pharmaceuticals Inc | COMPOSITIONS FORMULATED IN LIPIDS AND METHODS OF INHIBITING THE EXPRESSION OF EBOLA VIRUS GENE |
US8791087B2 (en) | 2009-08-21 | 2014-07-29 | Curna, Inc. | Treatment of ‘C terminus of HSP70-interacting protein’ (CHIP)related diseases by inhibition of natural antisense transcript to CHIP |
CA2771172C (en) | 2009-08-25 | 2021-11-30 | Opko Curna, Llc | Treatment of 'iq motif containing gtpase activating protein' (iqgap) related diseases by inhibition of natural antisense transcript to iqgap |
WO2011028950A1 (en) | 2009-09-02 | 2011-03-10 | Genentech, Inc. | Mutant smoothened and methods of using the same |
JP6175236B2 (ja) | 2009-09-25 | 2017-08-09 | カッパーアールエヌエー,インコーポレイテッド | フィラグリン(flg)の発現および活性の調整によるflg関連疾患の処置 |
CN102711826B (zh) | 2009-10-22 | 2017-03-29 | 霍夫曼-拉罗奇有限公司 | 用于调控巨噬细胞刺激性蛋白的hepsin活化的方法和组合物 |
KR20120136345A (ko) | 2009-10-30 | 2012-12-18 | 노오쓰웨스턴 유니버시티 | 주형화된 나노컨쥬게이트 |
KR102113306B1 (ko) | 2009-11-12 | 2020-05-21 | 더 유니버시티 오브 웨스턴 오스트레일리아 | 안티센스 분자 및 이를 이용한 질환 치료방법 |
PE20121584A1 (es) | 2009-11-30 | 2012-11-29 | Genentech Inc | Composiciones y metodos para el diagnostico y el tratamiento de tumores |
CA3044884A1 (en) | 2009-12-07 | 2011-06-16 | Arbutus Biopharma Corporation | Compositions for nucleic acid delivery |
EP2509991B1 (en) * | 2009-12-09 | 2015-11-11 | Nitto Denko Corporation | Modulation of hsp47 expression |
KR101823702B1 (ko) | 2009-12-16 | 2018-01-30 | 큐알엔에이, 인크. | 막 결합 전사 인자 펩티다제, 부위 1(mbtps1)에 대한 천연 안티센스 전사체의 억제에 의한 mbtps1 관련 질환의 치료 |
ES2749426T3 (es) | 2009-12-18 | 2020-03-20 | Univ British Columbia | Métodos y composiciones para administración de ácidos nucleicos |
CN102869776B (zh) | 2009-12-23 | 2017-06-23 | 库尔纳公司 | 通过抑制肝细胞生长因子(hgf)的天然反义转录物而治疗hgf相关疾病 |
RU2619185C2 (ru) | 2009-12-23 | 2017-05-12 | Курна, Инк. | Лечение заболеваний, связанных с разобщающим белком 2 (ucp2), путем ингибирования природного антисмыслового транскрипта к ucp2 |
WO2011090740A2 (en) | 2009-12-29 | 2011-07-28 | Opko Curna, Llc | Treatment of nuclear respiratory factor 1 (nrf1) related diseases by inhibition of natural antisense transcript to nrf1 |
US8962585B2 (en) | 2009-12-29 | 2015-02-24 | Curna, Inc. | Treatment of tumor protein 63 (p63) related diseases by inhibition of natural antisense transcript to p63 |
KR101853511B1 (ko) | 2009-12-31 | 2018-06-20 | 큐알엔에이, 인크. | 인슐린 수용체 기질 2 및 전사 인자 e3(tfe3)에 대한 천연 안티센스 전사체의 억제에 의한 irs2 관련된 질환의 치료 |
KR101878501B1 (ko) | 2010-01-04 | 2018-08-07 | 큐알엔에이, 인크. | 인터페론 조절 인자 8 (irf8)에 대한 자연 안티센스 전사체의 저해에 의한 인터페론 조절 인자 8 (irf8) 관련된 질환의 치료 |
KR101853509B1 (ko) | 2010-01-06 | 2018-04-30 | 큐알엔에이, 인크. | 췌장 발달 유전자에 대한 천연 안티센스 전사체의 억제에 의한 췌장 발달 유전자와 관련된 질환의 치료 |
CA2786535C (en) | 2010-01-11 | 2019-03-26 | Curna, Inc. | Treatment of sex hormone binding globulin (shbg) related diseases by inhibition of natural antisense transcript to shbg |
JP5981850B2 (ja) | 2010-01-25 | 2016-08-31 | カッパーアールエヌエー,インコーポレイテッド | RNaseH1に対する天然アンチセンス転写物の阻害によるRNaseH1関連疾患の治療 |
WO2011100131A2 (en) | 2010-01-28 | 2011-08-18 | Alnylam Pharmacuticals, Inc. | Monomers and oligonucleotides comprising cycloaddition adduct(s) |
WO2011094580A2 (en) | 2010-01-28 | 2011-08-04 | Alnylam Pharmaceuticals, Inc. | Chelated copper for use in the preparation of conjugated oligonucleotides |
CA2824843A1 (en) | 2010-02-04 | 2011-08-11 | Ico Therapeutics Inc. | Dosing regimens for treating and preventing ocular disorders using c-raf antisense |
JP5976548B2 (ja) | 2010-02-22 | 2016-08-23 | カッパーアールエヌエー,インコーポレイテッド | Pycr1に対する天然アンチセンス転写物の阻害によるピロリン−5−カルボン酸レダクターゼ1(pycr1)関連疾患の治療 |
WO2011105900A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-alpha (c8-alpha) and uses thereof |
WO2011105901A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 9 (c9) and uses thereof |
WO2011105902A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-beta (c8-beta) and uses thereof |
AR080243A1 (es) | 2010-02-23 | 2012-03-21 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores |
SG183374A1 (en) * | 2010-02-24 | 2012-09-27 | Arrowhead Res Corp | Compositions for targeted delivery of sirna |
US9624491B2 (en) | 2010-02-26 | 2017-04-18 | Memorial Sloan Kettering Cancer Center | Methods and compositions for the detection and treatment of cancer involving miRNAs and miRNA inhibitors and targets |
WO2011112516A1 (en) | 2010-03-08 | 2011-09-15 | Ico Therapeutics Inc. | Treating and preventing hepatitis c virus infection using c-raf kinase antisense oligonucleotides |
EP3210611B1 (en) | 2010-03-12 | 2019-08-21 | The Brigham and Women's Hospital, Inc. | Methods of treating vascular inflammatory disorders |
WO2011123468A1 (en) | 2010-03-29 | 2011-10-06 | Alnylam Pharmaceuticals, Inc. | Sirna therapy for transthyretin (ttr) related ocular amyloidosis |
WO2011123621A2 (en) | 2010-04-01 | 2011-10-06 | Alnylam Pharmaceuticals Inc. | 2' and 5' modified monomers and oligonucleotides |
US8980856B2 (en) | 2010-04-02 | 2015-03-17 | Curna, Inc. | Treatment of colony-stimulating factor 3 (CSF3) related diseases by inhibition of natural antisense transcript to CSF3 |
EP2555778A4 (en) | 2010-04-06 | 2014-05-21 | Alnylam Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR INHIBITING CD274 / PD-L1 GENE EXPRESSION |
WO2011127337A2 (en) | 2010-04-09 | 2011-10-13 | Opko Curna Llc | Treatment of fibroblast growth factor 21 (fgf21) related diseases by inhibition of natural antisense transcript to fgf21 |
ES2905656T3 (es) | 2010-04-12 | 2022-04-11 | Somalogic Operating Co Inc | Pirimidinas modificadas en posición 5 y su uso |
DK2558578T3 (en) | 2010-04-13 | 2016-01-25 | Life Technologies Corp | CONFIGURATIONS AND METHODS FOR INHIBITION OF nucleic acid function |
US20130260460A1 (en) | 2010-04-22 | 2013-10-03 | Isis Pharmaceuticals Inc | Conformationally restricted dinucleotide monomers and oligonucleotides |
US9725479B2 (en) | 2010-04-22 | 2017-08-08 | Ionis Pharmaceuticals, Inc. | 5′-end derivatives |
WO2011133876A2 (en) | 2010-04-22 | 2011-10-27 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising acyclic and abasic nucleosides and analogs |
EP3091027B1 (en) | 2010-04-28 | 2018-01-17 | Ionis Pharmaceuticals, Inc. | 5' modified nucleosides and oligomeric compounds prepared therefrom |
KR101869570B1 (ko) | 2010-04-28 | 2018-06-20 | 아이오니스 파마수티컬즈, 인코포레이티드 | 변형된 뉴클레오사이드 및 그로부터 제조된 올리고머 화합물 |
WO2011139695A2 (en) | 2010-04-28 | 2011-11-10 | Isis Pharmaceuticals, Inc. | Modified 5' diphosphate nucleosides and oligomeric compounds prepared therefrom |
US20110294868A1 (en) | 2010-04-29 | 2011-12-01 | Monia Brett P | Modulation of transthyretin expression |
US20130156845A1 (en) | 2010-04-29 | 2013-06-20 | Alnylam Pharmaceuticals, Inc. | Lipid formulated single stranded rna |
CA2798218A1 (en) | 2010-05-03 | 2011-11-10 | Curna, Inc. | Treatment of sirtuin (sirt) related diseases by inhibition of natural antisense transcript to a sirtuin (sirt) |
MA34291B1 (fr) | 2010-05-03 | 2013-06-01 | Genentech Inc | Compositions et méthodes de diagnostic et de traitement d'une tumeur |
TWI531370B (zh) | 2010-05-14 | 2016-05-01 | 可娜公司 | 藉由抑制par4天然反股轉錄本治療par4相關疾病 |
JP5917497B2 (ja) | 2010-05-26 | 2016-05-18 | カッパーアールエヌエー,インコーポレイテッド | メチオニンスルホキシドレダクターゼa(msra)に対する天然アンチセンス転写物の阻害によるmsra関連疾患の治療 |
EP2576783B1 (en) | 2010-05-26 | 2017-11-29 | CuRNA, Inc. | Treatment of atonal homolog 1 (atoh1) related diseases by inhibition of natural antisense transcript to atoh1 |
KR20200133284A (ko) | 2010-05-28 | 2020-11-26 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 변형된 서브유니트간 결합 및/또는 말단 그룹을 갖는 올리고뉴클레오타이드 유사체 |
JP6081910B2 (ja) | 2010-06-02 | 2017-02-15 | 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Alnylam Pharmaceuticals, Inc. | 肝線維症治療用組成物および肝線維症の治療法 |
US9638632B2 (en) | 2010-06-11 | 2017-05-02 | Vanderbilt University | Multiplexed interferometric detection system and method |
WO2011163121A1 (en) | 2010-06-21 | 2011-12-29 | Alnylam Pharmaceuticals, Inc. | Multifunctional copolymers for nucleic acid delivery |
CN103025873B (zh) | 2010-06-23 | 2018-05-08 | 库尔纳公司 | 通过抑制电压门控钠通道α亚基(SCNA)的天然反义转录物而治疗SCNA相关疾病 |
AU2011270896B9 (en) | 2010-06-24 | 2015-05-07 | Quark Pharmaceuticals, Inc. | Double stranded RNA compounds to RhoA and use thereof |
JP5998131B2 (ja) | 2010-07-14 | 2016-09-28 | カッパーアールエヌエー,インコーポレイテッド | Discslargehomolog(dlg)dlg1への天然アンチセンス転写物の阻害によるdlg関連疾患の治療 |
US20130202652A1 (en) | 2010-07-30 | 2013-08-08 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for delivery of active agents |
WO2012016184A2 (en) | 2010-07-30 | 2012-02-02 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for delivery of active agents |
JP6043285B2 (ja) | 2010-08-02 | 2016-12-14 | サーナ・セラピューティクス・インコーポレイテッドSirna Therapeutics,Inc. | 低分子干渉核酸(siNA)を用いたカテニン(カドヘリン結合型タンパク質)β1(CTNNB1)遺伝子発現のRNA干渉媒介性阻害 |
CN108676800B (zh) | 2010-08-17 | 2022-11-11 | 瑟纳治疗公司 | 使用短干扰核酸(siNA)的乙型肝炎病毒(HBV)基因表达的RNA干扰介导的抑制 |
EP3372684B1 (en) | 2010-08-24 | 2020-10-07 | Sirna Therapeutics, Inc. | Single-stranded rnai agents containing an internal, non-nucleic acid spacer |
EP2609106A4 (en) | 2010-08-26 | 2014-03-19 | Merck Sharp & Dohme | RNA INTERFERENCE-MEDIATED INHIBITION OF EXPRESSION OF PHD2 GENE (PROLYL HYDROXYLASE DOMAIN 2) USING SMALL INTERFERING NUCLEIC ACID (PANI) |
WO2012031243A2 (en) | 2010-09-03 | 2012-03-08 | Avi Biopharma, Inc. | dsRNA MOLECULES COMPRISING OLIGONUCLEOTIDE ANALOGS HAVING MODIFIED INTERSUBUNIT LINKAGES AND/OR TERMINAL GROUPS |
DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
SG10201508118WA (en) | 2010-09-30 | 2015-11-27 | Agency Science Tech & Res | Methods and reagents for detection and treatment of esophageal metaplasia |
AU2011312205B2 (en) | 2010-10-05 | 2015-08-13 | Curis, Inc. | Mutant smoothened and methods of using the same |
RU2624048C2 (ru) | 2010-10-06 | 2017-06-30 | Курна, Инк. | Лечение заболеваний, связанных с геном сиалидазы 4 (neu4), путем ингибирования природного антисмыслового транскрипта гена neu4 |
WO2012048113A2 (en) | 2010-10-07 | 2012-04-12 | The General Hospital Corporation | Biomarkers of cancer |
WO2012054723A2 (en) | 2010-10-22 | 2012-04-26 | Opko Curna Llc | Treatment of alpha-l-iduronidase (idua) related diseases by inhibition of natural antisense transcript to idua |
US20130210893A1 (en) | 2010-10-27 | 2013-08-15 | Curna, Inc. | Treatment of interferon-related developmental regulator 1 (ifrd1) related diseases by inhibition of natural antisense transcript to ifrd1 |
ES2663009T3 (es) | 2010-10-29 | 2018-04-10 | Sirna Therapeutics, Inc. | Inhibición de la expresión génica mediada por interferencia por ARN utilizando ácidos nucleicos de interferencia cortos (ANic) |
US9339513B2 (en) | 2010-11-09 | 2016-05-17 | Alnylam Pharmaceuticals, Inc. | Lipid formulated compositions and methods for inhibiting expression of Eg5 and VEGF genes |
AU2011325956B2 (en) | 2010-11-12 | 2016-07-14 | The General Hospital Corporation | Polycomb-associated non-coding RNAs |
US10000752B2 (en) | 2010-11-18 | 2018-06-19 | Curna, Inc. | Antagonat compositions and methods of use |
KR102010598B1 (ko) | 2010-11-23 | 2019-08-13 | 큐알엔에이, 인크. | Nanog에 대한 자연 안티센스 전사체의 저해에 의한 nanog 관련된 질환의 치료 |
EP2648763A4 (en) | 2010-12-10 | 2014-05-14 | Alnylam Pharmaceuticals Inc | COMPOSITIONS AND METHODS FOR EXPRESSION INHIBITION OF GENES KLF-1 AND BCL11A |
WO2012078967A2 (en) | 2010-12-10 | 2012-06-14 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for increasing erythropoietin (epo) production |
US20130344053A1 (en) | 2010-12-28 | 2013-12-26 | University Of Rochester | Methods of Modifying Insulin Signaling Using Biliverdin Reductase (BVR) and BVR Derived Peptides |
CA2824526C (en) | 2011-01-11 | 2020-07-07 | Alnylam Pharmaceuticals, Inc. | Pegylated lipids and their use for drug delivery |
US9045749B2 (en) | 2011-01-14 | 2015-06-02 | The General Hospital Corporation | Methods targeting miR-128 for regulating cholesterol/lipid metabolism |
EP2670411B1 (en) | 2011-02-02 | 2019-04-10 | Excaliard Pharmaceuticals, Inc. | Antisense compounds targeting connective tissue growth factor (ctgf) for use in a method of treating keloids or hypertrophic scars |
US20140044644A1 (en) | 2011-02-21 | 2014-02-13 | University Of Zurich | Ankyrin g and modulators thereof for the treatment of neurodegenerative disorders |
US9562853B2 (en) | 2011-02-22 | 2017-02-07 | Vanderbilt University | Nonaqueous backscattering interferometric methods |
EP2681314B1 (en) | 2011-03-03 | 2017-11-01 | Quark Pharmaceuticals, Inc. | Compositions and methods for treating lung disease and injury |
EP3674409A1 (en) | 2011-03-29 | 2020-07-01 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of tmprss6 gene |
US10196637B2 (en) | 2011-06-08 | 2019-02-05 | Nitto Denko Corporation | Retinoid-lipid drug carrier |
EP2718261B1 (en) | 2011-06-08 | 2016-02-24 | Nitto Denko Corporation | Compounds for targeting drug delivery and enhancing sirna activity |
TWI658830B (zh) | 2011-06-08 | 2019-05-11 | 日東電工股份有限公司 | Hsp47表現調控強化用類視色素脂質體 |
US9011903B2 (en) | 2011-06-08 | 2015-04-21 | Nitto Denko Corporation | Cationic lipids for therapeutic agent delivery formulations |
RU2620980C2 (ru) | 2011-06-09 | 2017-05-30 | Курна, Инк. | Лечение заболеваний, связанных с фратаксином (fxn), путем ингибирования природного антисмыслового транскрипта fxn |
US9068184B2 (en) | 2011-06-21 | 2015-06-30 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibition of expression of protein C (PROC) genes |
EP2723758B1 (en) | 2011-06-21 | 2018-06-20 | Alnylam Pharmaceuticals, Inc. | Angiopoietin-like 3 (angptl3) irna compostions and methods of use thereof |
JP6236385B2 (ja) | 2011-06-21 | 2017-11-22 | 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Alnylam Pharmaceuticals, Inc. | アポリポタンパク質c−iii(apoc3)の発現を阻害するための組成物及び方法 |
EP2723390B1 (en) | 2011-06-23 | 2017-12-27 | Alnylam Pharmaceuticals, Inc. | Serpina1 sirnas: compositions of matter and methods of treatment |
US20140227293A1 (en) | 2011-06-30 | 2014-08-14 | Trustees Of Boston University | Method for controlling tumor growth, angiogenesis and metastasis using immunoglobulin containing and proline rich receptor-1 (igpr-1) |
CN107365339A (zh) | 2011-07-19 | 2017-11-21 | 波涛生命科学有限公司 | 合成官能化核酸的方法 |
JP2014526887A (ja) | 2011-08-01 | 2014-10-09 | 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 | 造血幹細胞移植の成功率を改善する方法 |
EA029151B1 (ru) | 2011-09-06 | 2018-02-28 | Курна, Инк. | ЛЕЧЕНИЕ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АЛЬФА-СУБЪЕДИНИЦАМИ ПОТЕНЦИАЛЗАВИСИМЫХ НАТРИЕВЫХ КАНАЛОВ (SCNxA), С ПОМОЩЬЮ МАЛЫХ МОЛЕКУЛ |
EP2756080B1 (en) | 2011-09-14 | 2019-02-20 | Translate Bio MA, Inc. | Multimeric oligonucleotide compounds |
EP2755692B1 (en) | 2011-09-14 | 2020-11-25 | Northwestern University | Nanoconjugates able to cross the blood-brain barrier |
EP3456317A1 (en) | 2011-09-27 | 2019-03-20 | Alnylam Pharmaceuticals, Inc. | Di-aliphatic substituted pegylated lipids |
US10184151B2 (en) | 2011-10-11 | 2019-01-22 | The Brigham And Women's Hospital, Inc. | Micrornas in neurodegenerative disorders |
KR20140097398A (ko) | 2011-11-18 | 2014-08-06 | 사렙타 쎄러퓨틱스, 인코퍼레이티드 | 기능적으로-변형된 올리고뉴클레오티드 및 이의 서브유니트 |
DE12858350T1 (de) | 2011-12-16 | 2021-10-07 | Modernatx, Inc. | Modifizierte mrna zusammensetzungen |
LT2794627T (lt) | 2011-12-22 | 2019-01-10 | Alios Biopharma, Inc. | Pakeistieji nukleozidai, nukleotidai ir jų analogai |
US20140364484A1 (en) | 2012-01-12 | 2014-12-11 | Quark Pharmaceuticals, Inc. | Combination therapy for treating hearing and balance disorders |
WO2013138374A2 (en) | 2012-03-15 | 2013-09-19 | Curna, Inc. | Treatment of brain derived neurotrophic factor (bdnf) related diseases by inhibition of natural antisense transcript to bdnf |
USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
WO2013142255A2 (en) | 2012-03-22 | 2013-09-26 | University Of Miami | Multi-specific binding agents |
CN104411338A (zh) | 2012-04-02 | 2015-03-11 | 现代治疗公司 | 用于产生与人类疾病相关的生物制剂和蛋白质的修饰多核苷酸 |
EP3501550A1 (en) | 2012-04-02 | 2019-06-26 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of proteins associated with human disease |
US9133461B2 (en) | 2012-04-10 | 2015-09-15 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the ALAS1 gene |
EP2839005B1 (en) | 2012-04-20 | 2021-01-06 | Aptamir Therapeutics, Inc. | Mirna modulators of thermogenesis |
US9127274B2 (en) | 2012-04-26 | 2015-09-08 | Alnylam Pharmaceuticals, Inc. | Serpinc1 iRNA compositions and methods of use thereof |
EP2841572B1 (en) | 2012-04-27 | 2019-06-19 | Duke University | Genetic correction of mutated genes |
EP3358013B1 (en) | 2012-05-02 | 2020-06-24 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
US9273949B2 (en) | 2012-05-11 | 2016-03-01 | Vanderbilt University | Backscattering interferometric methods |
AU2013262649A1 (en) | 2012-05-16 | 2015-01-22 | Rana Therapeutics, Inc. | Compositions and methods for modulating smn gene family expression |
KR102028784B1 (ko) | 2012-05-16 | 2019-10-04 | 트랜슬레이트 바이오 인코포레이티드 | 유전자 발현을 조절하기 위한 조성물 및 방법 |
CA2879023C (en) | 2012-07-13 | 2017-03-28 | Wave Life Sciences Japan | Asymmetric auxiliary group |
WO2014022852A1 (en) | 2012-08-03 | 2014-02-06 | Aptamir Therapeutics, Inc. | Cell-specific delivery of mirna modulators for the treatment of obesity and related disorders |
WO2014043292A1 (en) | 2012-09-12 | 2014-03-20 | Quark Pharmaceuticals, Inc. | Double-stranded oligonucleotide molecules to p53 and methods of use thereof |
EP2895607B1 (en) | 2012-09-12 | 2021-05-05 | Quark Pharmaceuticals, Inc. | Double-stranded oligonucleotide molecules to ddit4 and methods of use thereof |
EP2908853B1 (en) | 2012-10-21 | 2018-12-05 | University Of Rochester | Thy1 (cd90) as a therapy to control adipose tissue accumulation |
US10548962B2 (en) | 2012-10-22 | 2020-02-04 | The Board Of Regents For Oklahoma State University | Use of the salmonella SPP type III secretion proteins as a protective vaccination |
US9950053B2 (en) | 2012-10-22 | 2018-04-24 | The Board Of Regents For Oklahoma State University | Use of the Salmonella SPP type III secretion proteins as a protective vaccination |
US9597380B2 (en) | 2012-11-26 | 2017-03-21 | Modernatx, Inc. | Terminally modified RNA |
WO2014088920A1 (en) | 2012-12-06 | 2014-06-12 | Merck Sharp & Dohme Corp. | Disulfide masked prodrug compositions and methods |
EP2946014A2 (en) | 2013-01-17 | 2015-11-25 | Moderna Therapeutics, Inc. | Signal-sensor polynucleotides for the alteration of cellular phenotypes |
US20150366890A1 (en) | 2013-02-25 | 2015-12-24 | Trustees Of Boston University | Compositions and methods for treating fungal infections |
WO2014159813A1 (en) | 2013-03-13 | 2014-10-02 | Moderna Therapeutics, Inc. | Long-lived polynucleotide molecules |
PL2970974T3 (pl) | 2013-03-14 | 2018-01-31 | Alnylam Pharmaceuticals Inc | Kompozycje komponentu C5 dopełniacza iRNA i sposoby ich zastosowania |
EP2971010B1 (en) | 2013-03-14 | 2020-06-10 | ModernaTX, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
EA035882B1 (ru) | 2013-03-14 | 2020-08-27 | Сарепта Терапьютикс, Инк. | Антисмысловые олигонуклеотиды, обеспечивающие пропуск экзонов, для лечения мышечной дистрофии |
WO2014144978A2 (en) | 2013-03-15 | 2014-09-18 | Sarepta Therapeutics, Inc. | Improved compositions for treating muscular dystrophy |
US8980864B2 (en) | 2013-03-15 | 2015-03-17 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US9937231B2 (en) | 2013-03-27 | 2018-04-10 | The General Hospital Corporation | Methods and agents for treating Alzheimer's disease |
WO2014172698A1 (en) | 2013-04-19 | 2014-10-23 | Isis Pharmaceuticals, Inc. | Compositions and methods for modulation nucleic acids through nonsense mediated decay |
MY176712A (en) | 2013-05-22 | 2020-08-19 | Alnylam Pharmaceuticals Inc | Serpina1 irna compositions and methods of use thereof |
WO2014197938A1 (en) | 2013-06-13 | 2014-12-18 | Antisense Therapeutics Ltd | Combination therapy |
EP3019619B1 (en) | 2013-07-11 | 2021-08-25 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
ES2750608T3 (es) | 2013-07-25 | 2020-03-26 | Exicure Inc | Construcciones esféricas a base de ácido nucleico como agentes inmunoestimulantes para uso profiláctico y terapéutico |
JP2016531122A (ja) | 2013-08-08 | 2016-10-06 | ザ スクリップス リサーチ インスティテュートThe Scripps Research Institute | 非天然ヌクレオチドの取り込みによるインビトロの核酸の部位特異的な酵素標識のための方法 |
EP3041938A1 (en) | 2013-09-03 | 2016-07-13 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2015034928A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
TWI669393B (zh) | 2013-10-02 | 2019-08-21 | 艾爾妮蘭製藥公司 | 抑制lect2基因表現之組合物及方法 |
EP3052521A1 (en) | 2013-10-03 | 2016-08-10 | Moderna Therapeutics, Inc. | Polynucleotides encoding low density lipoprotein receptor |
PE20161130A1 (es) | 2013-10-04 | 2016-11-25 | Icahn School Med Mount Sinai | Composiciones y metodos para inhibir la expresion del gen alas1 |
MX371440B (es) | 2013-11-21 | 2020-01-30 | Somalogic Inc | Composiciones nucleotidicas modificadas con citidina-5-carboxamida y metodos relacionados con las mismas. |
EP3985118A1 (en) | 2013-11-22 | 2022-04-20 | MiNA Therapeutics Limited | C/ebp alpha short activating rna compositions and methods of use |
CA2844640A1 (en) | 2013-12-06 | 2015-06-06 | The University Of British Columbia | Method for treatment of castration-resistant prostate cancer |
AU2014362262B2 (en) | 2013-12-12 | 2021-05-13 | Alnylam Pharmaceuticals, Inc. | Complement component iRNA compositions and methods of use thereof |
US9274117B2 (en) | 2013-12-21 | 2016-03-01 | Catholic University Industry Academic | Use of SIRT7 as novel cancer therapy target and method for treating cancer using the same |
KR20230152178A (ko) | 2014-01-16 | 2023-11-02 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
US11236389B2 (en) | 2014-01-31 | 2022-02-01 | Temple University Of The Commonwealth System Of Higher Education | BAG3 as a target for therapy of heart failure |
WO2015120075A2 (en) | 2014-02-04 | 2015-08-13 | Genentech, Inc. | Mutant smoothened and methods of using the same |
KR102389968B1 (ko) | 2014-02-11 | 2022-04-25 | 알닐람 파마슈티칼스 인코포레이티드 | 케토헥소키나제(KHK) iRNA 조성물 및 그의 사용 방법 |
TWI638047B (zh) | 2014-04-09 | 2018-10-11 | 史基普研究協會 | 藉由核酸三磷酸酯轉運子將非天然或經修飾的核苷三磷酸酯輸入至細胞中 |
ES2932304T3 (es) | 2014-04-17 | 2023-01-17 | Biogen Ma Inc | Composiciones y métodos para la modulación del empalme de SMN2 en un sujeto |
WO2015171918A2 (en) | 2014-05-07 | 2015-11-12 | Louisiana State University And Agricultural And Mechanical College | Compositions and uses for treatment thereof |
TW201607559A (zh) | 2014-05-12 | 2016-03-01 | 阿尼拉製藥公司 | 治療serpinc1相關疾患之方法和組成物 |
GB201408623D0 (en) | 2014-05-15 | 2014-07-02 | Santaris Pharma As | Oligomers and oligomer conjugates |
WO2015179724A1 (en) | 2014-05-22 | 2015-11-26 | Alnylam Pharmaceuticals, Inc. | Angiotensinogen (agt) irna compositions and methods of use thereof |
KR102290205B1 (ko) | 2014-06-04 | 2021-08-20 | 엑시큐어, 인크. | 예방 또는 치료 용도를 위한 리포솜성 구형 핵산에 의한 면역 조절인자의 다가 전달 |
HRP20220379T1 (hr) | 2014-06-10 | 2022-05-27 | Erasmus University Medical Center Rotterdam | Antisense oligonukleotidi korisni u liječenju pompeove bolesti |
WO2015200697A1 (en) | 2014-06-25 | 2015-12-30 | The General Hospital Corporation | Targeting human satellite ii (hsatii) |
AU2015289583A1 (en) | 2014-07-16 | 2017-02-02 | Modernatx, Inc. | Chimeric polynucleotides |
EP3171895A1 (en) | 2014-07-23 | 2017-05-31 | Modernatx, Inc. | Modified polynucleotides for the production of intrabodies |
JP7081923B2 (ja) | 2014-07-31 | 2022-06-07 | ユーエイビー リサーチ ファンデーション | アポe模倣ペプチド及び血漿コレステロールを取り除くためのより高い効果 |
EP3185910A4 (en) | 2014-08-29 | 2018-01-10 | Children's Medical Center Corporation | Methods and compositions for the treatment of cancer |
WO2016033424A1 (en) | 2014-08-29 | 2016-03-03 | Genzyme Corporation | Methods for the prevention and treatment of major adverse cardiovascular events using compounds that modulate apolipoprotein b |
WO2016040589A1 (en) | 2014-09-12 | 2016-03-17 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting complement component c5 and methods of use thereof |
WO2016044271A2 (en) | 2014-09-15 | 2016-03-24 | Children's Medical Center Corporation | Methods and compositions to increase somatic cell nuclear transfer (scnt) efficiency by removing histone h3-lysine trimethylation |
EP3198012B1 (en) | 2014-09-26 | 2019-09-04 | University of Massachusetts | Rna-modulating agents |
EP3207138B1 (en) | 2014-10-17 | 2020-07-15 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting aminolevulinic acid synthase-1 (alas1) and uses thereof |
WO2016069906A1 (en) | 2014-10-29 | 2016-05-06 | Massachusetts Eye And Ear Infirmary | Efficient delivery of therapeutic molecules to cells of the inner ear |
EP3212221B1 (en) | 2014-10-29 | 2023-12-06 | Massachusetts Eye & Ear Infirmary | Efficient delivery of therapeutic molecules in vitro and in vivo |
WO2016069694A2 (en) | 2014-10-30 | 2016-05-06 | Alnylam Pharmaceuticals, Inc. | Polynucleotide agents targeting serpinc1 (at3) and methods of use thereof |
JOP20200092A1 (ar) | 2014-11-10 | 2017-06-16 | Alnylam Pharmaceuticals Inc | تركيبات iRNA لفيروس الكبد B (HBV) وطرق لاستخدامها |
CN113846101A (zh) | 2014-11-17 | 2021-12-28 | 阿尔尼拉姆医药品有限公司 | 载脂蛋白C3(APOC3)iRNA组合物及其使用方法 |
WO2016081911A2 (en) | 2014-11-21 | 2016-05-26 | Northwestern University | The sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates |
EP4088741A1 (en) | 2014-12-08 | 2022-11-16 | The Board of Regents of the University of Texas System | Lipocationic polymers and uses thereof |
JP6997623B2 (ja) | 2014-12-12 | 2022-02-04 | エム. ウルフ、トッド | オリゴヌクレオチドを利用して細胞内の核酸を編集するための組成物および方法 |
AU2015364508A1 (en) | 2014-12-18 | 2017-07-06 | Alnylam Pharmaceuticals, Inc. | ReversirTM compounds |
WO2016118812A1 (en) | 2015-01-23 | 2016-07-28 | Vanderbilt University | A robust interferometer and methods of using same |
JP6929791B2 (ja) | 2015-02-09 | 2021-09-01 | デューク ユニバーシティ | エピゲノム編集のための組成物および方法 |
WO2016130806A2 (en) | 2015-02-13 | 2016-08-18 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
US20180200387A1 (en) | 2015-02-23 | 2018-07-19 | Crispr Therapeutics Ag | Materials and methods for treatment of human genetic diseases including hemoglobinopathies |
WO2016164463A1 (en) | 2015-04-07 | 2016-10-13 | The General Hospital Corporation | Methods for reactivating genes on the inactive x chromosome |
MX2017012610A (es) | 2015-04-08 | 2018-03-16 | Alnylam Pharmaceuticals Inc | Composiciones y metodos para inhibir la expresion del gen lect2. |
WO2016196897A1 (en) | 2015-06-04 | 2016-12-08 | Sarepta Therapeutics, Inc. | Methods and compounds for treatment of lymphocyte-related diseases and conditions |
EP3307316A1 (en) | 2015-06-12 | 2018-04-18 | Alnylam Pharmaceuticals, Inc. | Complement component c5 irna compositions and methods of use thereof |
WO2016205323A1 (en) | 2015-06-18 | 2016-12-22 | Alnylam Pharmaceuticals, Inc. | Polynucleotde agents targeting hydroxyacid oxidase (glycolate oxidase, hao1) and methods of use thereof |
WO2016209862A1 (en) | 2015-06-23 | 2016-12-29 | Alnylam Pharmaceuticals, Inc. | Glucokinase (gck) irna compositions and methods of use thereof |
CN108139375A (zh) | 2015-06-26 | 2018-06-08 | 贝斯以色列女执事医疗中心股份有限公司 | 靶向髓样衍生的抑制细胞中的四跨膜蛋白33(tspan33)的癌症疗法 |
AU2016287499B2 (en) | 2015-06-29 | 2022-08-04 | Caris Science, Inc. | Therapeutic oligonucleotides |
WO2017011286A1 (en) | 2015-07-10 | 2017-01-19 | Alnylam Pharmaceuticals, Inc. | Insulin-like growth factor binding protein, acid labile subunit (igfals) and insulin-like growth factor 1 (igf-1) irna compositions and methods of use thereof |
AU2016295168B2 (en) | 2015-07-17 | 2021-08-19 | Alnylam Pharmaceuticals, Inc. | Multi-targeted single entity conjugates |
EP3328873A4 (en) | 2015-07-28 | 2019-04-10 | Caris Science, Inc. | TARGETED OLIGONUCLEOTIDES |
SG10202007937SA (en) | 2015-09-02 | 2020-09-29 | Alnylam Pharmaceuticals Inc | PROGRAMMED CELL DEATH 1 LIGAND 1 (PD-L1) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
EP3950003A1 (en) | 2015-09-14 | 2022-02-09 | The Board of Regents of the University of Texas System | Lipocationic dendrimers and uses thereof |
AU2016339053A1 (en) | 2015-09-24 | 2018-04-12 | Crispr Therapeutics Ag | Novel family of RNA-programmable endonucleases and their uses in genome editing and other applications |
EP3362571A4 (en) | 2015-10-13 | 2019-07-10 | Duke University | GENOMIC ENGINEERING WITH TYPE I CRISPRISMS IN EUKARYOTIC CELLS |
WO2017072590A1 (en) | 2015-10-28 | 2017-05-04 | Crispr Therapeutics Ag | Materials and methods for treatment of duchenne muscular dystrophy |
CA3007424A1 (en) | 2015-11-05 | 2017-05-11 | Children's Hospital Los Angeles | "mobilizing leukemia cells" |
CN109328231A (zh) | 2015-11-06 | 2019-02-12 | 克里斯普治疗股份公司 | 用于治疗1a型糖原贮积病的材料和方法 |
AU2016355178B9 (en) | 2015-11-19 | 2019-05-30 | Massachusetts Institute Of Technology | Lymphocyte antigen CD5-like (CD5L)-interleukin 12B (p40) heterodimers in immunity |
AU2016364667A1 (en) | 2015-12-01 | 2018-06-21 | Crispr Therapeutics Ag | Materials and methods for treatment of Alpha-1 antitrypsin deficiency |
CA3007152A1 (en) | 2015-12-07 | 2017-06-15 | Erasmus University Medical Center Rotterdam | Enzymatic replacement therapy and antisense therapy for pompe disease |
US11761007B2 (en) | 2015-12-18 | 2023-09-19 | The Scripps Research Institute | Production of unnatural nucleotides using a CRISPR/Cas9 system |
WO2017109757A1 (en) | 2015-12-23 | 2017-06-29 | Crispr Therapeutics Ag | Materials and methods for treatment of amyotrophic lateral sclerosis and/or frontal temporal lobular degeneration |
EP3408649B1 (en) | 2016-01-29 | 2023-06-14 | Vanderbilt University | Free-solution response function interferometry |
US20190038771A1 (en) | 2016-02-02 | 2019-02-07 | Crispr Therapeutics Ag | Materials and methods for treatment of severe combined immunodeficiency (scid) or omenn syndrome |
AU2017213826A1 (en) | 2016-02-04 | 2018-08-23 | Curis, Inc. | Mutant smoothened and methods of using the same |
US20190112353A1 (en) | 2016-02-18 | 2019-04-18 | Crispr Therapeutics Ag | Materials and methods for treatment of severe combined immunodeficiency (scid) or omenn syndrome |
CA3054284A1 (en) | 2016-02-25 | 2017-08-31 | The Brigham And Women's Hospital, Inc. | Treatment methods for fibrosis targeting smoc2 |
WO2017158422A1 (en) | 2016-03-16 | 2017-09-21 | Crispr Therapeutics Ag | Materials and methods for treatment of hereditary haemochromatosis |
KR20190008843A (ko) | 2016-03-18 | 2019-01-25 | 카리스 싸이언스, 인코포레이티드 | 올리고뉴클레오티드 프로브 및 이의 용도 |
SG10202010261YA (en) | 2016-04-18 | 2020-11-27 | Crispr Therapeutics Ag | Materials and methods for treatment of hemoglobinopathies |
WO2017191503A1 (en) | 2016-05-05 | 2017-11-09 | Crispr Therapeutics Ag | Materials and methods for treatment of hemoglobinopathies |
CN109414408B (zh) | 2016-05-16 | 2022-03-29 | 得克萨斯州大学系统董事会 | 阳离子磺酰胺氨基脂质和两亲性两性离子氨基脂质 |
AU2017271579B2 (en) | 2016-05-25 | 2023-10-19 | Caris Science, Inc. | Oligonucleotide probes and uses thereof |
EP3469083A1 (en) | 2016-06-10 | 2019-04-17 | Alnylam Pharmaceuticals, Inc. | COMPLEMENT COMPONENT C5 iRNA COMPOSITIONS AND METHODS OF USE THEREOF FOR TREATING PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) |
DK3475295T3 (da) | 2016-06-24 | 2022-10-24 | Scripps Research Inst | Hidtil ukendt nukleosidtriphosphat-transportør og anvendelser deraf |
US11174469B2 (en) | 2016-06-29 | 2021-11-16 | Crispr Therapeutics Ag | Materials and methods for treatment of Amyotrophic Lateral Sclerosis (ALS) and other related disorders |
WO2018002812A1 (en) | 2016-06-29 | 2018-01-04 | Crispr Therapeutics Ag | Materials and methods for treatment of myotonic dystrophy type 1 (dm1) and other related disorders |
US11564997B2 (en) | 2016-06-29 | 2023-01-31 | Crispr Therapeutics Ag | Materials and methods for treatment of friedreich ataxia and other related disorders |
AU2017292173B2 (en) | 2016-07-06 | 2022-01-13 | Vertex Pharmaceuticals Incorporated | Materials and methods for treatment of pain related disorders |
JP7305534B2 (ja) | 2016-07-06 | 2023-07-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | 疼痛関連障害を処置するための物質及び方法 |
WO2018007871A1 (en) | 2016-07-08 | 2018-01-11 | Crispr Therapeutics Ag | Materials and methods for treatment of transthyretin amyloidosis |
CA3030701A1 (en) | 2016-07-11 | 2018-01-18 | Translate Bio Ma, Inc. | Nucleic acid conjugates and uses thereof |
WO2018020323A2 (en) | 2016-07-25 | 2018-02-01 | Crispr Therapeutics Ag | Materials and methods for treatment of fatty acid disorders |
NL2017295B1 (en) | 2016-08-05 | 2018-02-14 | Univ Erasmus Med Ct Rotterdam | Antisense oligomeric compound for Pompe disease |
NL2017294B1 (en) | 2016-08-05 | 2018-02-14 | Univ Erasmus Med Ct Rotterdam | Natural cryptic exon removal by pairs of antisense oligonucleotides. |
EP3532638A4 (en) | 2016-10-31 | 2020-07-29 | University of Massachusetts | TARGETING MICROARN-101-3 P IN CARCINOTHERAPY |
TWI788312B (zh) | 2016-11-23 | 2023-01-01 | 美商阿尼拉製藥公司 | 絲胺酸蛋白酶抑制因子A1 iRNA組成物及其使用方法 |
CN110191955B (zh) | 2016-12-13 | 2024-05-31 | 西雅图儿童医院(Dba西雅图儿童研究所) | 在体外和体内对工程化的细胞中表达的化学物质诱导的信号传导复合物进行外源性药物激活的方法 |
WO2018112320A1 (en) | 2016-12-16 | 2018-06-21 | Alnylam Pharmaceuticals, Inc. | Methods for treating or preventing ttr-associated diseases using transthyretin (ttr) irna compositions |
US11197928B2 (en) | 2017-01-13 | 2021-12-14 | Board Of Regents, The University Of Texas System | Sustained production of high affinity antigen specific antibody by high dose BAFF receptor-targeting mAb-siRNA conjugate |
CN110446785B (zh) | 2017-01-23 | 2024-04-26 | 瑞泽恩制药公司 | Hsd17b13变体及其应用 |
US20200040061A1 (en) | 2017-02-22 | 2020-02-06 | Crispr Therapeutics Ag | Materials and methods for treatment of early onset parkinson's disease (park1) and other synuclein, alpha (snca) gene related conditions or disorders |
CN110662838B (zh) | 2017-02-22 | 2024-05-28 | 克里斯珀医疗股份公司 | 用于基因编辑的组合物和方法 |
WO2018154439A1 (en) | 2017-02-22 | 2018-08-30 | Crispr Therapeutics Ag | Materials and methods for treatment of spinocerebellar ataxia type 1 (sca1) and other spinocerebellar ataxia type 1 protein (atxn1) gene related conditions or disorders |
WO2018154459A1 (en) | 2017-02-22 | 2018-08-30 | Crispr Therapeutics Ag | Materials and methods for treatment of primary hyperoxaluria type 1 (ph1) and other alanine-glyoxylate aminotransferase (agxt) gene related conditions or disorders |
WO2018154462A2 (en) | 2017-02-22 | 2018-08-30 | Crispr Therapeutics Ag | Materials and methods for treatment of spinocerebellar ataxia type 2 (sca2) and other spinocerebellar ataxia type 2 protein (atxn2) gene related conditions or disorders |
MA50278A (fr) | 2017-04-18 | 2020-02-26 | Alnylam Pharmaceuticals Inc | Méthodes pour le traitement de sujets atteints d'une infection par le virus de l'hépatite b (vhb) |
EP3612232A1 (en) | 2017-04-21 | 2020-02-26 | The Broad Institute, Inc. | Targeted delivery to beta cells |
WO2018209270A1 (en) | 2017-05-11 | 2018-11-15 | Northwestern University | Adoptive cell therapy using spherical nucleic acids (snas) |
AU2018367896B2 (en) | 2017-05-12 | 2023-06-01 | Crispr Therapeutics Ag | Materials and methods for engineering cells and uses thereof in immuno-oncology |
TWI821192B (zh) | 2017-07-11 | 2023-11-11 | 美商新索思股份有限公司 | 非天然核苷酸之導入及其方法 |
CA3069868A1 (en) | 2017-07-13 | 2019-01-17 | Alnylam Pharmaceuticals Inc. | Lactate dehydrogenase a (ldha) irna compositions and methods of use thereof |
BR112020002271A2 (pt) | 2017-08-03 | 2020-07-28 | Synthorx, Inc. | conjugados de citocina para o tratamento de doenças proliferativas e infecciosas |
US20200208152A1 (en) | 2017-09-08 | 2020-07-02 | Mina Therapeutics Limited | Stabilized sarna compositions and methods of use |
TW201920669A (zh) | 2017-09-08 | 2019-06-01 | 英商美納治療公司 | HNF4a saRNA組成物和使用方法 |
WO2019055460A1 (en) | 2017-09-13 | 2019-03-21 | The Children's Medical Center Corporation | COMPOSITIONS AND METHODS FOR THE TREATMENT OF TRANSPOSON-ASSOCIATED DISEASES |
CA3079172A1 (en) | 2017-10-17 | 2019-04-25 | Crispr Therapeutics Ag | Compositions and methods for gene editing for hemophilia a |
EP3701029A1 (en) | 2017-10-26 | 2020-09-02 | Vertex Pharmaceuticals Incorporated | Materials and methods for treatment of hemoglobinopathies |
AU2018360697A1 (en) | 2017-11-01 | 2020-05-14 | Alnylam Pharmaceuticals, Inc. | Complement component C3 iRNA compositions and methods of use thereof |
MA50579A (fr) | 2017-11-09 | 2020-09-16 | Crispr Therapeutics Ag | Systèmes crispr/cas ou crispr/cpf1 à auto-inactivation (sin) et leurs utilisations |
WO2019100039A1 (en) | 2017-11-20 | 2019-05-23 | Alnylam Pharmaceuticals, Inc. | Serum amyloid p component (apcs) irna compositions and methods of use thereof |
AU2018372763A1 (en) | 2017-11-21 | 2020-05-28 | Bayer Healthcare Llc | Materials and methods for treatment of autosomal dominant Retinitis Pigmentosa |
EP3720473A1 (en) | 2017-12-05 | 2020-10-14 | Vertex Pharmaceuticals Incorporated | Crispr-cas9 modified cd34+ human hematopoietic stem and progenitor cells and uses thereof |
WO2019118935A1 (en) | 2017-12-14 | 2019-06-20 | Casebia Therapeutics Limited Liability Partnership | Novel rna-programmable endonuclease systems and their use in genome editing and other applications |
AU2018388484A1 (en) | 2017-12-18 | 2020-07-30 | Alnylam Pharmaceuticals, Inc. | High mobility group box-1 (HMGB1) iRNA compositions and methods of use thereof |
CA3084633A1 (en) | 2017-12-21 | 2019-06-27 | Crispr Therapeutics Ag | Materials and methods for treatment of usher syndrome type 2a and/or non-syndromic autosomal recessive retinitis pigmentosa (arrp) |
JP7402163B2 (ja) | 2017-12-21 | 2023-12-20 | クリスパー セラピューティクス アーゲー | 2a型アッシャー症候群の処置のための材料および方法 |
CA3088180A1 (en) | 2018-01-12 | 2019-07-18 | Crispr Therapeutics Ag | Compositions and methods for gene editing by targeting transferrin |
US20190233816A1 (en) | 2018-01-26 | 2019-08-01 | Massachusetts Institute Of Technology | Structure-guided chemical modification of guide rna and its applications |
US11268077B2 (en) | 2018-02-05 | 2022-03-08 | Vertex Pharmaceuticals Incorporated | Materials and methods for treatment of hemoglobinopathies |
MA51787A (fr) | 2018-02-05 | 2020-12-16 | Vertex Pharma | Substances et méthodes de traitement d'hémoglobinopathies |
WO2019161310A1 (en) | 2018-02-16 | 2019-08-22 | Casebia Therapeutics Limited Liability Partnership | Compositions and methods for gene editing by targeting fibrinogen-alpha |
KR20200127207A (ko) | 2018-02-26 | 2020-11-10 | 신톡스, 인크. | Il-15 접합체 및 이의 용도 |
JP2021518139A (ja) | 2018-03-19 | 2021-08-02 | クリスパー セラピューティクス アーゲー | 新規rnaプログラム可能エンドヌクレアーゼ系およびその使用 |
EP4051799A2 (en) | 2018-03-30 | 2022-09-07 | Rheinische Friedrich-Wilhelms-Universität Bonn | Aptamers for targeted activaton of t cell-mediated immunity |
US20210155959A1 (en) | 2018-04-06 | 2021-05-27 | Children's Medical Center Corporation | Compositions and methods for somatic cell reprogramming and modulating imprinting |
US11566246B2 (en) | 2018-04-12 | 2023-01-31 | Mina Therapeutics Limited | SIRT1-saRNA compositions and methods of use |
WO2019204668A1 (en) | 2018-04-18 | 2019-10-24 | Casebia Therapeutics Limited Liability Partnership | Compositions and methods for knockdown of apo(a) by gene editing for treatment of cardiovascular disease |
AU2019255370B2 (en) | 2018-04-19 | 2023-11-02 | Checkmate Pharmaceuticals, Inc. | Synthetic RIG-I-like receptor agonists |
KR20210016353A (ko) | 2018-04-27 | 2021-02-15 | 시애틀 칠드런즈 호스피탈 디/비/에이 시애틀 칠드런즈 리서치 인스티튜트 | 라파마이신 내성 세포 |
SG11202010910QA (en) | 2018-05-07 | 2020-12-30 | Alnylam Pharmaceuticals Inc | Extrahepatic delivery |
TW202016304A (zh) | 2018-05-14 | 2020-05-01 | 美商阿尼拉製藥公司 | 血管收縮素原(AGT)iRNA組成物及其使用方法 |
CN112673103A (zh) | 2018-08-13 | 2021-04-16 | 阿尔尼拉姆医药品有限公司 | 乙型肝炎病毒(HBV)dsRNA剂组合物及其使用方法 |
WO2020037125A1 (en) | 2018-08-16 | 2020-02-20 | Alnylam Pharmaceuticals Inc. | Compositions and methods for inhibiting expression of the lect2 gene |
WO2020047229A1 (en) | 2018-08-29 | 2020-03-05 | University Of Massachusetts | Inhibition of protein kinases to treat friedreich ataxia |
JP2022500003A (ja) | 2018-09-18 | 2022-01-04 | 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Alnylam Pharmaceuticals, Inc. | ケトヘキソキナーゼ(KHK)iRNA組成物およびその使用方法 |
TW202028465A (zh) | 2018-09-28 | 2020-08-01 | 美商阿尼拉製藥公司 | 甲狀腺素運載蛋白(TTR)iRNA組成物及其治療或預防TTR相關眼部疾病之使用方法 |
CA3116885A1 (en) | 2018-10-17 | 2020-04-23 | Crispr Therapeutics Ag | Compositions and methods for delivering transgenes |
US10913951B2 (en) | 2018-10-31 | 2021-02-09 | University of Pittsburgh—of the Commonwealth System of Higher Education | Silencing of HNF4A-P2 isoforms with siRNA to improve hepatocyte function in liver failure |
AU2019405961A1 (en) | 2018-12-20 | 2021-07-22 | Humabs Biomed Sa | Combination HBV therapy |
EP3898977A1 (en) | 2018-12-20 | 2021-10-27 | Praxis Precision Medicines, Inc. | Compositions and methods for the treatment of kcnt1 related disorders |
US11452738B2 (en) | 2019-01-04 | 2022-09-27 | Empirico Inc. | Treatment of thymic stromal lymphopoietin (TSLP) related diseases by inhibition of long-form TSLP transcripts |
SG11202107669WA (en) | 2019-01-16 | 2021-08-30 | Genzyme Corp | Serpinc1 irna compositions and methods of use thereof |
CN114949240A (zh) | 2019-02-06 | 2022-08-30 | 新索思股份有限公司 | Il-2缀合物及其使用方法 |
AU2020221340A1 (en) | 2019-02-15 | 2021-09-16 | Bayer Healthcare Llc | Gene editing for hemophilia A with improved Factor VIII expression |
WO2020171889A1 (en) | 2019-02-19 | 2020-08-27 | University Of Rochester | Blocking lipid accumulation or inflammation in thyroid eye disease |
SG11202109741VA (en) | 2019-03-12 | 2021-10-28 | Crispr Therapeutics Ag | Novel high fidelity rna-programmable endonuclease systems and uses thereof |
US20220211740A1 (en) | 2019-04-12 | 2022-07-07 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
TW202108764A (zh) | 2019-05-13 | 2021-03-01 | 美商維爾生物科技公司 | 用於治療b型肝炎病毒(hbv)感染之組成物及方法 |
US20220211743A1 (en) | 2019-05-17 | 2022-07-07 | Alnylam Pharmaceuticals, Inc. | Oral delivery of oligonucleotides |
KR20220034109A (ko) | 2019-06-14 | 2022-03-17 | 더 스크립스 리서치 인스티튜트 | 반합성 유기체의 복제, 전사 및 번역을 위한 시약 및 방법 |
WO2021022108A2 (en) | 2019-08-01 | 2021-02-04 | Alnylam Pharmaceuticals, Inc. | CARBOXYPEPTIDASE B2 (CPB2) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
WO2021022109A1 (en) | 2019-08-01 | 2021-02-04 | Alnylam Pharmaceuticals, Inc. | SERPIN FAMILY F MEMBER 2 (SERPINF2) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
EP4013870A1 (en) | 2019-08-13 | 2022-06-22 | Alnylam Pharmaceuticals, Inc. | Small ribosomal protein subunit 25 (rps25) irna agent compositions and methods of use thereof |
CA3150163A1 (en) | 2019-08-15 | 2021-02-18 | Synthorx, Inc. | Immuno oncology combination therapies with il-2 conjugates |
US20220281911A1 (en) | 2019-08-19 | 2022-09-08 | Mina Therapeutics Limited | Oligonucleotide conjugate compositions and methods of use |
AU2020337869A1 (en) | 2019-08-23 | 2022-03-03 | Synthorx, Inc. | IL-15 conjugates and uses thereof |
AU2020343255A1 (en) | 2019-09-03 | 2022-03-24 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of the LECT2 gene |
TW202124385A (zh) | 2019-09-10 | 2021-07-01 | 美商欣爍克斯公司 | 治療自體免疫疾病之il-2接合物及使用方法 |
EP4038189A1 (en) | 2019-10-04 | 2022-08-10 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing ugt1a1 gene expression |
US20240141358A1 (en) | 2019-10-18 | 2024-05-02 | Alnylam Pharmaceuticals, Inc. | Solute carrier family member irna compositions and methods of use thereof |
TW202134435A (zh) | 2019-10-22 | 2021-09-16 | 美商阿尼拉製藥公司 | 補體成分c3 irna組成物及其使用方法 |
WO2021081353A1 (en) | 2019-10-23 | 2021-04-29 | Checkmate Pharmaceuticals, Inc. | Synthetic rig-i-like receptor agonists |
WO2021087325A1 (en) | 2019-11-01 | 2021-05-06 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing dnajb1-prkaca fusion gene expression |
EP4051795A1 (en) | 2019-11-01 | 2022-09-07 | Alnylam Pharmaceuticals, Inc. | Huntingtin (htt) irna agent compositions and methods of use thereof |
MX2022005251A (es) | 2019-11-04 | 2022-06-08 | Synthorx Inc | Conjugados de interleuquina 10 y sus usos. |
EP4055165A1 (en) | 2019-11-06 | 2022-09-14 | Alnylam Pharmaceuticals, Inc. | Transthyretin (ttr) irna compositions and methods of use thereof for treating or preventing ttr-associated ocular diseases |
US20230016929A1 (en) | 2019-11-06 | 2023-01-19 | Alnylam Pharmaceuticals, Inc. | Extrahepatic delivery |
TW202132568A (zh) | 2019-11-13 | 2021-09-01 | 美商阿尼拉製藥公司 | 用於治療血管收縮素原相關病症之方法及組成物 |
EP4061945A1 (en) | 2019-11-22 | 2022-09-28 | Alnylam Pharmaceuticals, Inc. | Ataxin3 (atxn3) rnai agent compositions and methods of use thereof |
BR112022011417A2 (pt) | 2019-12-13 | 2022-08-30 | Alnylam Pharmaceuticals Inc | Composições do agente de irna da fase de leitura aberta 72 do cromossomo humano 9 (c9orf72) e métodos de uso das mesmas |
TW202138559A (zh) | 2019-12-16 | 2021-10-16 | 美商阿尼拉製藥公司 | 含類PATATIN磷脂酶結構域3(PNPLA3)iRNA組成物及其使用方法 |
EP4077674A1 (en) | 2019-12-18 | 2022-10-26 | Alia Therapeutics S.R.L. | Compositions and methods for treating retinitis pigmentosa |
WO2021154941A1 (en) | 2020-01-31 | 2021-08-05 | Alnylam Pharmaceuticals, Inc. | Complement component c5 irna compositions for use in the treatment of amyotrophic lateral sclerosis (als) |
WO2021163066A1 (en) | 2020-02-10 | 2021-08-19 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing vegf-a expression |
EP4107265A1 (en) | 2020-02-18 | 2022-12-28 | Alnylam Pharmaceuticals, Inc. | Apolipoprotein c3 (apoc3) irna compositions and methods of use thereof |
EP4114947A1 (en) | 2020-03-05 | 2023-01-11 | Alnylam Pharmaceuticals, Inc. | Complement component c3 irna compositions and methods of use thereof for treating or preventing complement component c3-associated diseases |
IL296109A (en) | 2020-03-06 | 2022-11-01 | Alnylam Pharmaceuticals Inc | Ketohexokinase (khk) IRNA compositions and methods of using them |
CN115461460A (zh) | 2020-03-06 | 2022-12-09 | 阿尔尼拉姆医药品有限公司 | 用于抑制转甲状腺素蛋白(ttr)的表达的组合物和方法 |
WO2021188611A1 (en) | 2020-03-18 | 2021-09-23 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for treating subjects having a heterozygous alanine-glyoxylate aminotransferase gene (agxt) variant |
WO2021195307A1 (en) | 2020-03-26 | 2021-09-30 | Alnylam Pharmaceuticals, Inc. | Coronavirus irna compositions and methods of use thereof |
EP4127171A2 (en) | 2020-03-30 | 2023-02-08 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for silencing dnajc15 gene expression |
AR121769A1 (es) | 2020-04-06 | 2022-07-06 | Alnylam Pharmaceuticals Inc | Composiciones y métodos para el silenciamiento de la expresión de myoc |
WO2021206917A1 (en) | 2020-04-07 | 2021-10-14 | Alnylam Pharmaceuticals, Inc. | ANGIOTENSIN-CONVERTING ENZYME 2 (ACE2) iRNA COMPOSITIONS AND METHODS OF USE THEREOF |
MX2022012561A (es) | 2020-04-07 | 2022-11-07 | Alnylam Pharmaceuticals Inc | Composiciones y metodos para silenciar la expresion de la subunidad alfa tipo ix dependiente del voltaje del canal de sodio (scn9a). |
WO2021206922A1 (en) | 2020-04-07 | 2021-10-14 | Alnylam Pharmaceuticals, Inc. | Transmembrane serine protease 2 (tmprss2) irna compositions and methods of use thereof |
AU2021263554A1 (en) | 2020-04-27 | 2022-12-08 | Alnylam Pharmaceuticals, Inc. | Apolipoprotein E (APOE) iRNA agent compositions and methods of use thereof |
MX2022013606A (es) | 2020-04-30 | 2023-01-16 | Alnylam Pharmaceuticals Inc | Composiciones de ácido ribonucleico interferente (arni) del factor b de complemento (cfb) y métodos de uso de las mismas. |
WO2021231692A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of otoferlin (otof) |
EP4150088A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of argininosuccinate synthetase (ass1) |
EP4150087A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of gap junction protein beta 2 (gjb2) |
WO2021231673A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of leucine rich repeat kinase 2 (lrrk2) |
WO2021231691A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of retinoschisin 1 (rsi) |
EP4150077A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of transmembrane channel-like protein 1 (tmc1) |
WO2021231680A1 (en) | 2020-05-15 | 2021-11-18 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of methyl-cpg binding protein 2 (mecp2) |
EP4150078A1 (en) | 2020-05-15 | 2023-03-22 | Korro Bio, Inc. | Methods and compositions for the adar-mediated editing of argininosuccinate lyase (asl) |
EP4153746A1 (en) | 2020-05-21 | 2023-03-29 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting marc1 gene expression |
KR20230016201A (ko) | 2020-05-22 | 2023-02-01 | 웨이브 라이프 사이언시스 리미티드 | 이중 가닥 올리고뉴클레오티드 조성물 및 이와 관련된 방법 |
US11408000B2 (en) | 2020-06-03 | 2022-08-09 | Triplet Therapeutics, Inc. | Oligonucleotides for the treatment of nucleotide repeat expansion disorders associated with MSH3 activity |
EP4162050A1 (en) | 2020-06-09 | 2023-04-12 | Alnylam Pharmaceuticals, Inc. | Rnai compositions and methods of use thereof for delivery by inhalation |
MX2022015149A (es) | 2020-06-18 | 2023-01-11 | Alnylam Pharmaceuticals Inc | Composiciones de acido ribonucleico de interferencia (arni) de xantina dehidrogenasa (xdh) y metodos de uso de las mismas. |
JP2023531520A (ja) | 2020-06-24 | 2023-07-24 | ヴィア・バイオテクノロジー・インコーポレイテッド | 操作されたb型肝炎ウイルス中和抗体およびその使用 |
CN116209465A (zh) | 2020-06-25 | 2023-06-02 | 新索思股份有限公司 | 用il-2缀合物与抗egfr抗体的免疫肿瘤学组合疗法 |
US20230257745A1 (en) | 2020-07-10 | 2023-08-17 | Alnylam Pharmaceuticals, Inc. | Circular siRNAs |
IL299771A (en) | 2020-07-10 | 2023-03-01 | Inst Nat Sante Rech Med | Methods and compounds for the treatment of epilepsy |
WO2022066847A1 (en) | 2020-09-24 | 2022-03-31 | Alnylam Pharmaceuticals, Inc. | Dipeptidyl peptidase 4 (dpp4) irna compositions and methods of use thereof |
US20220290136A1 (en) | 2020-09-30 | 2022-09-15 | Crispr Therapeutics Ag | Materials and methods for treatment of amyotrophic lateral sclerosis |
JP2023544413A (ja) | 2020-10-05 | 2023-10-23 | 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 | Gタンパク質共役受容体75(GPR75)iRNA組成物およびその使用方法 |
EP4225375A1 (en) | 2020-10-09 | 2023-08-16 | Synthorx, Inc. | Immuno oncology therapies with il-2 conjugates |
IL301611A (en) | 2020-10-09 | 2023-05-01 | Synthorx Inc | Combined immuno-oncology treatment with pairs of IL-2 and pembrolizumab |
WO2022087329A1 (en) | 2020-10-23 | 2022-04-28 | Alnylam Pharmaceuticals, Inc. | Mucin 5b (muc5b) irna compositions and methods of use thereof |
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WO2022174101A1 (en) | 2021-02-12 | 2022-08-18 | Synthorx, Inc. | Skin cancer combination therapy with il-2 conjugates and cemiplimab |
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EP4298220A1 (en) | 2021-02-25 | 2024-01-03 | Alnylam Pharmaceuticals, Inc. | Prion protein (prnp) irna compositions and methods of use thereof |
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WO2022192519A1 (en) | 2021-03-12 | 2022-09-15 | Alnylam Pharmaceuticals, Inc. | Glycogen synthase kinase 3 alpha (gsk3a) irna compositions and methods of use thereof |
CA3214137A1 (en) | 2021-03-26 | 2022-09-29 | Mina Therapeutics Limited | Tmem173 sarna compositions and methods of use |
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EP4314293A1 (en) | 2021-04-01 | 2024-02-07 | Alnylam Pharmaceuticals, Inc. | Proline dehydrogenase 2 (prodh2) irna compositions and methods of use thereof |
WO2022226291A1 (en) | 2021-04-22 | 2022-10-27 | Dana-Farber Cancer Institute, Inc. | Compositions and methods for treating cancer |
CA3216106A1 (en) | 2021-04-26 | 2022-11-03 | Alnylam Pharmaceuticals, Inc. | Transmembrane protease, serine 6 (tmprss6) irna compositions and methods of use thereof |
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WO2022245583A1 (en) | 2021-05-18 | 2022-11-24 | Alnylam Pharmaceuticals, Inc. | Sodium-glucose cotransporter-2 (sglt2) irna compositions and methods of use thereof |
WO2022246023A1 (en) | 2021-05-20 | 2022-11-24 | Korro Bio, Inc. | Methods and compositions for adar-mediated editing |
WO2022256283A2 (en) | 2021-06-01 | 2022-12-08 | Korro Bio, Inc. | Methods for restoring protein function using adar |
WO2022256395A1 (en) | 2021-06-02 | 2022-12-08 | Alnylam Pharmaceuticals, Inc. | Patatin-like phospholipase domain containing 3 (pnpla3) irna compositions and methods of use thereof |
WO2022256534A1 (en) | 2021-06-03 | 2022-12-08 | Synthorx, Inc. | Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab |
WO2022256290A2 (en) | 2021-06-04 | 2022-12-08 | Alnylam Pharmaceuticals, Inc. | HUMAN CHROMOSOME 9 OPEN READING FRAME 72 (C9ORF72) iRNA AGENT COMPOSITIONS AND METHODS OF USE THEREOF |
JP2024523000A (ja) | 2021-06-08 | 2024-06-25 | 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 | シュタルガルト病及び/又は網膜結合タンパク質4(rbp4)関連障害を治療又は予防するための組成物及び方法 |
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EP4352214A1 (en) | 2021-06-11 | 2024-04-17 | Bayer AG | Type v rna programmable endonuclease systems |
US20230194709A9 (en) | 2021-06-29 | 2023-06-22 | Seagate Technology Llc | Range information detection using coherent pulse sets with selected waveform characteristics |
EP4363574A1 (en) | 2021-06-29 | 2024-05-08 | Korro Bio, Inc. | Methods and compositions for adar-mediated editing |
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AR126675A1 (es) | 2021-08-03 | 2023-11-01 | Alnylam Pharmaceuticals Inc | COMPOSICIONES DE ARNi CONTRA LA TRANSTIRRETINA (TTR) Y SUS MÉTODOS DE USO |
WO2023014765A1 (en) | 2021-08-04 | 2023-02-09 | Alnylam Pharmaceuticals, Inc. | iRNA COMPOSITIONS AND METHODS FOR SILENCING ANGIOTENSINOGEN (AGT) |
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EP4144841A1 (en) | 2021-09-07 | 2023-03-08 | Bayer AG | Novel small rna programmable endonuclease systems with impoved pam specificity and uses thereof |
WO2023044370A2 (en) | 2021-09-17 | 2023-03-23 | Alnylam Pharmaceuticals, Inc. | Irna compositions and methods for silencing complement component 3 (c3) |
WO2023044094A1 (en) | 2021-09-20 | 2023-03-23 | Alnylam Pharmaceuticals, Inc. | Inhibin subunit beta e (inhbe) modulator compositions and methods of use thereof |
CN118369427A (zh) | 2021-10-15 | 2024-07-19 | 阿尔尼拉姆医药品有限公司 | 肝外递送irna组合物及其使用方法 |
US20230241118A1 (en) | 2021-10-20 | 2023-08-03 | University Of Rochester | Rejuvenation treatment of age-related white matter loss |
AU2022370009A1 (en) | 2021-10-22 | 2024-05-16 | Korro Bio, Inc. | Methods and compositions for disrupting nrf2-keap1 protein interaction by adar mediated rna editing |
KR20240095325A (ko) | 2021-10-29 | 2024-06-25 | 알닐람 파마슈티칼스 인코포레이티드 | 보체 인자 b (cfb) irna 조성물 및 이의 사용 방법 |
TW202334418A (zh) | 2021-10-29 | 2023-09-01 | 美商艾拉倫製藥股份有限公司 | 杭丁頓(HTT)iRNA劑組成物及其使用方法 |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023122573A1 (en) | 2021-12-20 | 2023-06-29 | Synthorx, Inc. | Head and neck cancer combination therapy comprising an il-2 conjugate and pembrolizumab |
WO2023118349A1 (en) | 2021-12-21 | 2023-06-29 | Alia Therapeutics Srl | Type ii cas proteins and applications thereof |
WO2023118068A1 (en) | 2021-12-23 | 2023-06-29 | Bayer Aktiengesellschaft | Novel small type v rna programmable endonuclease systems |
WO2023122750A1 (en) | 2021-12-23 | 2023-06-29 | Synthorx, Inc. | Cancer combination therapy with il-2 conjugates and cetuximab |
WO2023141314A2 (en) | 2022-01-24 | 2023-07-27 | Alnylam Pharmaceuticals, Inc. | Heparin sulfate biosynthesis pathway enzyme irna agent compositions and methods of use thereof |
US12037616B2 (en) | 2022-03-01 | 2024-07-16 | Crispr Therapeutics Ag | Methods and compositions for treating angiopoietin-like 3 (ANGPTL3) related conditions |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023194359A1 (en) | 2022-04-04 | 2023-10-12 | Alia Therapeutics Srl | Compositions and methods for treatment of usher syndrome type 2a |
WO2023220744A2 (en) | 2022-05-13 | 2023-11-16 | Alnylam Pharmaceuticals, Inc. | Single-stranded loop oligonucleotides |
WO2023237587A1 (en) | 2022-06-10 | 2023-12-14 | Bayer Aktiengesellschaft | Novel small type v rna programmable endonuclease systems |
WO2024006999A2 (en) | 2022-06-30 | 2024-01-04 | Alnylam Pharmaceuticals, Inc. | Cyclic-disulfide modified phosphate based oligonucleotide prodrugs |
EP4311579A1 (en) | 2022-07-29 | 2024-01-31 | Association Française contre les Myopathies | B cell-specific mab-sirna conjugates improve myasthenia |
WO2024035952A1 (en) | 2022-08-12 | 2024-02-15 | Remix Therapeutics Inc. | Methods and compositions for modulating splicing at alternative splice sites |
WO2024039776A2 (en) | 2022-08-18 | 2024-02-22 | Alnylam Pharmaceuticals, Inc. | Universal non-targeting sirna compositions and methods of use thereof |
WO2024044352A1 (en) | 2022-08-26 | 2024-02-29 | The General Hospital Corporation | Methods and compositions for prognosis and treatment of dilated cardiomyopathy and heart failure |
WO2024059165A1 (en) | 2022-09-15 | 2024-03-21 | Alnylam Pharmaceuticals, Inc. | 17b-hydroxysteroid dehydrogenase type 13 (hsd17b13) irna compositions and methods of use thereof |
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WO2024105162A1 (en) | 2022-11-16 | 2024-05-23 | Alia Therapeutics Srl | Type ii cas proteins and applications thereof |
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WO2024136899A1 (en) | 2022-12-21 | 2024-06-27 | Synthorx, Inc. | Cancer therapy with il-2 conjugates and chimeric antigen receptor therapies |
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WO2024149810A2 (en) | 2023-01-11 | 2024-07-18 | Alia Therapeutics Srl | Type ii cas proteins and applications thereof |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3310337A1 (de) * | 1983-03-22 | 1984-09-27 | Europäisches Laboratorium für Molekularbiologie (EMBL), 6900 Heidelberg | Verfahren zur durchfuehrung von hybridisierungsreaktionen |
JPH03503894A (ja) * | 1988-03-25 | 1991-08-29 | ユニバーシィティ オブ バージニア アランミ パテンツ ファウンデイション | オリゴヌクレオチド n‐アルキルホスホラミデート |
US5166195A (en) * | 1990-05-11 | 1992-11-24 | Isis Pharmaceuticals, Inc. | Antisense inhibitors of the human immunodeficiency virus phosphorothioate oligonucleotides |
AU1245392A (en) * | 1991-02-13 | 1992-09-15 | Austin Research Institute, The | Conjugate molecules |
-
1990
- 1990-07-27 US US07/558,663 patent/US5138045A/en not_active Expired - Lifetime
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1991
- 1991-06-10 CA CA002087731A patent/CA2087731A1/en not_active Abandoned
- 1991-06-10 JP JP3513696A patent/JPH06500087A/ja active Pending
- 1991-06-10 AT AT91915260T patent/ATE159025T1/de not_active IP Right Cessation
- 1991-06-10 AU AU84184/91A patent/AU649067B2/en not_active Ceased
- 1991-06-10 EP EP91915260A patent/EP0544757B1/en not_active Expired - Lifetime
- 1991-06-10 BR BR919106701A patent/BR9106701A/pt not_active Application Discontinuation
- 1991-06-10 WO PCT/US1991/004086 patent/WO1992002531A1/en active IP Right Grant
- 1991-06-10 DE DE69127903T patent/DE69127903T2/de not_active Expired - Fee Related
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BR9106701A (pt) | 1993-06-29 |
AU8418491A (en) | 1992-03-02 |
AU649067B2 (en) | 1994-05-12 |
EP0544757A1 (en) | 1993-06-09 |
ATE159025T1 (de) | 1997-10-15 |
EP0544757A4 (en) | 1994-07-06 |
CA2087731A1 (en) | 1992-01-28 |
WO1992002531A1 (en) | 1992-02-20 |
US5138045A (en) | 1992-08-11 |
DE69127903D1 (de) | 1997-11-13 |
EP0544757B1 (en) | 1997-10-08 |
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