NZ544637A - Lipid encapsulated interfering RNA - Google Patents

Info

Publication number

NZ544637A

NZ544637A NZ544637A NZ54463704A NZ544637A NZ 544637 A NZ544637 A NZ 544637A NZ 544637 A NZ544637 A NZ 544637A NZ 54463704 A NZ54463704 A NZ 54463704A NZ 544637 A NZ544637 A NZ 544637A

Authority

NZ

New Zealand

Prior art keywords

lipid

nucleic acid

particle

peg

sirna

Prior art date

2003-07-16

Links

• Espacenet
• Global Dossier
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• 150000002632 lipids Chemical class 0.000 title claims abstract description 223
• 230000002452 interceptive effect Effects 0.000 title description 30
• 239000002245 particle Substances 0.000 claims abstract description 285
• 108020004459 Small interfering RNA Proteins 0.000 claims abstract description 132
• 239000000203 mixture Substances 0.000 claims abstract description 113
• 108090000623 proteins and genes Proteins 0.000 claims abstract description 107
• -1 cationic lipid Chemical class 0.000 claims abstract description 106
• 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 77
• 230000014509 gene expression Effects 0.000 claims abstract description 76
• 230000002776 aggregation Effects 0.000 claims abstract description 34
• 238000004220 aggregation Methods 0.000 claims abstract description 34
• 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 33
• 230000030279 gene silencing Effects 0.000 claims abstract description 25
• 239000003814 drug Substances 0.000 claims abstract description 15
• 229920002647 polyamide Polymers 0.000 claims abstract description 15
• 239000004952 Polyamide Substances 0.000 claims abstract description 14
• 210000004027 cell Anatomy 0.000 claims description 89
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 54
• 239000013612 plasmid Substances 0.000 claims description 54
• 238000012384 transportation and delivery Methods 0.000 claims description 47
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 44
• 201000010099 disease Diseases 0.000 claims description 34
• 238000001990 intravenous administration Methods 0.000 claims description 30
• NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims description 27
• 125000003729 nucleotide group Chemical group 0.000 claims description 26
• 239000002773 nucleotide Substances 0.000 claims description 25
• 229940106189 ceramide Drugs 0.000 claims description 22
• 235000012000 cholesterol Nutrition 0.000 claims description 22
• 238000001727 in vivo Methods 0.000 claims description 22
• MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 claims description 21
• 208000035475 disorder Diseases 0.000 claims description 20
• 229910052757 nitrogen Inorganic materials 0.000 claims description 20
• 239000007864 aqueous solution Substances 0.000 claims description 19
• WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 13
• 241000124008 Mammalia Species 0.000 claims description 12
• 208000006454 hepatitis Diseases 0.000 claims description 12
• 231100000283 hepatitis Toxicity 0.000 claims description 12
• 230000015556 catabolic process Effects 0.000 claims description 11
• 238000006731 degradation reaction Methods 0.000 claims description 11
• 150000003904 phospholipids Chemical class 0.000 claims description 11
• 230000002018 overexpression Effects 0.000 claims description 9
• KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 101710163270 Nuclease Proteins 0.000 claims description 7
• UMGXUWVIJIQANV-UHFFFAOYSA-M didecyl(dimethyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCC[N+](C)(C)CCCCCCCCCC UMGXUWVIJIQANV-UHFFFAOYSA-M 0.000 claims description 7
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
• KSXTUUUQYQYKCR-LQDDAWAPSA-M 2,3-bis[[(z)-octadec-9-enoyl]oxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC(=O)OCC(C[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC KSXTUUUQYQYKCR-LQDDAWAPSA-M 0.000 claims description 5
• PSLWZOIUBRXAQW-UHFFFAOYSA-M dimethyl(dioctadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC PSLWZOIUBRXAQW-UHFFFAOYSA-M 0.000 claims description 4
• 208000005176 Hepatitis C Diseases 0.000 claims description 3
• UAKOZKUVZRMOFN-JDVCJPALSA-M dimethyl-bis[(z)-octadec-9-enyl]azanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCC[N+](C)(C)CCCCCCCC\C=C/CCCCCCCC UAKOZKUVZRMOFN-JDVCJPALSA-M 0.000 claims description 3
• 208000002672 hepatitis B Diseases 0.000 claims description 3
• GLGLUQVVDHRLQK-WRBBJXAJSA-N n,n-dimethyl-2,3-bis[(z)-octadec-9-enoxy]propan-1-amine Chemical compound CCCCCCCC\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/CCCCCCCC GLGLUQVVDHRLQK-WRBBJXAJSA-N 0.000 claims description 3
• LDGWQMRUWMSZIU-LQDDAWAPSA-M 2,3-bis[(z)-octadec-9-enoxy]propyl-trimethylazanium;chloride Chemical compound [Cl-].CCCCCCCC\C=C/CCCCCCCCOCC(C[N+](C)(C)C)OCCCCCCCC\C=C/CCCCCCCC LDGWQMRUWMSZIU-LQDDAWAPSA-M 0.000 claims 1
• 210000005229 liver cell Anatomy 0.000 claims 1
• 238000009472 formulation Methods 0.000 abstract description 29
• 150000007523 nucleic acids Chemical class 0.000 description 135
• 102000039446 nucleic acids Human genes 0.000 description 122
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• 238000000034 method Methods 0.000 description 111
• 239000004055 small Interfering RNA Substances 0.000 description 108
• 239000000243 solution Substances 0.000 description 72
• 108091032973 (ribonucleotides)n+m Proteins 0.000 description 67
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
• 125000002091 cationic group Chemical group 0.000 description 58
• 206010028980 Neoplasm Diseases 0.000 description 53
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
• 239000005089 Luciferase Substances 0.000 description 48
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 44
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• 239000002502 liposome Substances 0.000 description 39
• 239000000047 product Substances 0.000 description 37
• 108060001084 Luciferase Proteins 0.000 description 35
• 238000002360 preparation method Methods 0.000 description 29
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
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• 108020004414 DNA Proteins 0.000 description 26
• 238000000338 in vitro Methods 0.000 description 26
• 102000040650 (ribonucleotides)n+m Human genes 0.000 description 25
• MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 24
• 239000003960 organic solvent Substances 0.000 description 24
• 210000001519 tissue Anatomy 0.000 description 24
• 238000003556 assay Methods 0.000 description 23
• 210000004185 liver Anatomy 0.000 description 22
• 239000002953 phosphate buffered saline Substances 0.000 description 22
• 238000011282 treatment Methods 0.000 description 22
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
• 238000006243 chemical reaction Methods 0.000 description 21
• 241000699670 Mus sp. Species 0.000 description 20
• 230000000694 effects Effects 0.000 description 20
• 230000000087 stabilizing effect Effects 0.000 description 20
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
• 239000012071 phase Substances 0.000 description 17
• 125000002252 acyl group Chemical group 0.000 description 16
• 238000009396 hybridization Methods 0.000 description 16
• 238000002156 mixing Methods 0.000 description 16
• 239000000523 sample Substances 0.000 description 16
• 230000015572 biosynthetic process Effects 0.000 description 15
• 150000008104 phosphatidylethanolamines Chemical class 0.000 description 15
• 102000004169 proteins and genes Human genes 0.000 description 15
• 238000004809 thin layer chromatography Methods 0.000 description 15
• LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 14
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• 210000004072 lung Anatomy 0.000 description 14
• 210000000056 organ Anatomy 0.000 description 14
• 229920000642 polymer Polymers 0.000 description 14
• 239000002904 solvent Substances 0.000 description 14
• 239000007858 starting material Substances 0.000 description 14
• KPNIMSUWPAYOQV-UHFFFAOYSA-N 1,2-di(tetradecoxy)propan-1-amine Chemical compound CCCCCCCCCCCCCCOC(C)C(N)OCCCCCCCCCCCCCC KPNIMSUWPAYOQV-UHFFFAOYSA-N 0.000 description 13
• 238000013296 A/J mouse Methods 0.000 description 13
• 108091028043 Nucleic acid sequence Proteins 0.000 description 13
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
• 238000002347 injection Methods 0.000 description 13
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• 238000003752 polymerase chain reaction Methods 0.000 description 12
• 238000001890 transfection Methods 0.000 description 12
• JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 11
• 239000000232 Lipid Bilayer Substances 0.000 description 11
• 150000001982 diacylglycerols Chemical class 0.000 description 11
• 230000002209 hydrophobic effect Effects 0.000 description 11
• 230000007935 neutral effect Effects 0.000 description 11
• 210000002966 serum Anatomy 0.000 description 11
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• 229940067605 phosphatidylethanolamines Drugs 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
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• 125000000217 alkyl group Chemical group 0.000 description 9
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• YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 8
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• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
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• ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 8
• 150000001783 ceramides Chemical class 0.000 description 8
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• MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 8
• VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 8
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