ES2609014T3 - Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico - Google Patents
Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico Download PDFInfo
- Publication number
- ES2609014T3 ES2609014T3 ES10183024.8T ES10183024T ES2609014T3 ES 2609014 T3 ES2609014 T3 ES 2609014T3 ES 10183024 T ES10183024 T ES 10183024T ES 2609014 T3 ES2609014 T3 ES 2609014T3
- Authority
- ES
- Spain
- Prior art keywords
- sequence
- rna
- precursor
- manipulated
- transgenic
- 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.)
- Expired - Lifetime
Links
- 108020004459 Small interfering RNA Proteins 0.000 title description 7
- 238000004519 manufacturing process Methods 0.000 title description 4
- 230000030279 gene silencing Effects 0.000 title 1
- 238000012226 gene silencing method Methods 0.000 title 1
- 238000001727 in vivo Methods 0.000 title 1
- 238000000034 method Methods 0.000 abstract description 17
- 108020005093 RNA Precursors Proteins 0.000 abstract description 16
- 108020004999 messenger RNA Proteins 0.000 abstract description 8
- 239000002773 nucleotide Substances 0.000 abstract description 7
- 125000003729 nucleotide group Chemical group 0.000 abstract description 7
- 108090000623 proteins and genes Proteins 0.000 abstract description 7
- 239000002243 precursor Substances 0.000 abstract description 5
- 108091032973 (ribonucleotides)n+m Proteins 0.000 abstract description 3
- 230000000295 complement effect Effects 0.000 abstract 2
- 241001465754 Metazoa Species 0.000 description 22
- 230000009261 transgenic effect Effects 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 16
- 108700019146 Transgenes Proteins 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 210000001671 embryonic stem cell Anatomy 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 102000020233 phosphotransferase Human genes 0.000 description 5
- 229920001184 polypeptide Polymers 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 4
- 108091030071 RNAI Proteins 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 230000009368 gene silencing by RNA Effects 0.000 description 4
- 210000004602 germ cell Anatomy 0.000 description 4
- 108020004707 nucleic acids Proteins 0.000 description 4
- 102000039446 nucleic acids Human genes 0.000 description 4
- 150000007523 nucleic acids Chemical class 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- 241000252212 Danio rerio Species 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000700584 Simplexvirus Species 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 210000002257 embryonic structure Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 238000000520 microinjection Methods 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000013598 vector Substances 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 241000612703 Augusta Species 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000244203 Caenorhabditis elegans Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 1
- 108700002304 Drosophila can Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241000991587 Enterovirus C Species 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 244000062730 Melissa officinalis Species 0.000 description 1
- 235000010654 Melissa officinalis Nutrition 0.000 description 1
- 244000246386 Mentha pulegium Species 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 235000004357 Mentha x piperita Nutrition 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241000282579 Pan Species 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- -1 Primogel TM Polymers 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038997 Retroviral infections Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 101710137500 T7 RNA polymerase Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 241000021375 Xenogenes Species 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- XYWMWLADMNOAAA-UHFFFAOYSA-N acetic acid;buta-1,3-diene Chemical compound CC(O)=O.C=CC=C XYWMWLADMNOAAA-UHFFFAOYSA-N 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229920000249 biocompatible polymer Polymers 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- IECPWNUMDGFDKC-MZJAQBGESA-N fusidic acid Chemical class O[C@@H]([C@@H]12)C[C@H]3\C(=C(/CCC=C(C)C)C(O)=O)[C@@H](OC(C)=O)C[C@]3(C)[C@@]2(C)CC[C@@H]2[C@]1(C)CC[C@@H](O)[C@H]2C IECPWNUMDGFDKC-MZJAQBGESA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006801 homologous recombination Effects 0.000 description 1
- 238000002744 homologous recombination Methods 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229960001047 methyl salicylate Drugs 0.000 description 1
- 238000002493 microarray Methods 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000009452 underexpressoin Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/111—General methods applicable to biologically active non-coding nucleic acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/10—Cells modified by introduction of foreign genetic material
- C12N5/12—Fused cells, e.g. hybridomas
- C12N5/16—Animal cells
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/11—Antisense
- C12N2310/111—Antisense spanning the whole gene, or a large part of it
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/50—Physical structure
- C12N2310/53—Physical structure partially self-complementary or closed
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2320/00—Applications; Uses
- C12N2320/30—Special therapeutic applications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2330/00—Production
- C12N2330/30—Production chemically synthesised
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2330/00—Production
- C12N2330/50—Biochemical production, i.e. in a transformed host cell
- C12N2330/51—Specially adapted vectors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2517/00—Cells related to new breeds of animals
- C12N2517/02—Cells from transgenic animals
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2799/00—Uses of viruses
- C12N2799/02—Uses of viruses as vector
- C12N2799/021—Uses of viruses as vector for the expression of a heterologous nucleic acid
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2830/00—Vector systems having a special element relevant for transcription
- C12N2830/008—Vector systems having a special element relevant for transcription cell type or tissue specific enhancer/promoter combination
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Biotechnology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Veterinary Medicine (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Physics & Mathematics (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Virology (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Cardiology (AREA)
Abstract
Un método para preparar un precursor de ARN manipulado que comprende las etapas de: (a) seleccionar una secuencia de ARN mensajero (ARNm) de un gen diana; y (b) manipular un ARN precuros que comprende i) una primera porción de tallo que comprende una secuencia de 18 a 40 nucleótidos que es complementaria a la secuencia de ARNm seleccionada; ii) una segunda porción de tallo que comprende una secuencia de 18 a 40 nucleótidos que es suficientemente complementaria a la secuencia de 18 a 40 nucleótidos de la primera porción de tallo para hibridar con la primera porción de tallo para formar un tallo dúplex; y iii) una porción de bucle de al menos 4 nucleótidos que conecta las dos porciones de tallo; en el que el precursor es capaz de ser procesado por Dicer.
Description
5
10
15
20
25
30
35
40
45
50
55
objetivo indicará si la ingeniería del precursor creó un pre-ARNsi capaz de mediación de secuencias específicas ARNi.
Animales Transgénicos
Los precursores de ARN manipulados de la invención pueden expresarse en animales transgénicos. Estos animales representan un sistema modelo para el estudio de trastornos que son causados por, o exacerbados por, sobreexpresión o subexpresión (en comparación con tipo silvestre o normal) de ácidos nucleicos (y sus polipéptidos codificados) dirigidos a la destrucción por el precursor de ARN manipulado (ARNsi) y para el desarrollo de agentes terapéuticos que modulan la expresión o actividad de ácidos nucleicos o polipéptidos destinados a la destrucción.
Los animales transgénicos pueden ser animales de granja (cerdos, cabras, ovejas, vacas, caballos, conejos y similares), roedores (tales como ratas, cobayas y ratones), primates no humanos (por ejemplo, babuinos, monos y chimpancés), y animales domésticos (por ejemplo, perros y gatos). Pueden usarse invertebrados tales como Caenorhabditis elegans o Drosophila, así como vertebrados no mamíferos tales como peces (por ejemplo, pez cebra) o aves (por ejemplo, pollos). Los precursores de ARN manipulados con tallos de 18 a 30 nucleótidos de longitud se prefieren para uso en mamíferos, tales como ratones.
Se puede identificar un animal fundador transgénico basado en la presencia de un transgén que codifica los nuevos precursores de ARN en su genoma y/o expresión del transgén en tejidos o células de los animales, por ejemplo, usando PCR o análisis de Northern . La expresión se confirma mediante una disminución de la expresión (ARN o proteína) de la secuencia diana.
Se puede usar un animal fundador transgénico para engendrar animales adicionales que portan el transgén. Además, los animales transgénicos que llevan un transgén que codifica los precursores de ARN pueden ser cruzados además con otros animales transgénicos que portan otros transgenes. Además, las células obtenidas del animal fundador transgénico o de su progenie pueden cultivarse para establecer líneas celulares primarias, secundarias o inmortales que contienen el transgén.
Procedimientos para hacer animales transgénicos, no humanos
Se han utilizado varios métodos para obtener animales no humanos transgénicos, que son animales que han obtenido un gen adicional mediante la introducción de un transgén en sus células (por ejemplo, las células somáticas y las células germinales) o en una línea germinal antepasada. En algunos casos, los animales transgénicos pueden ser generados por instalaciones comerciales (por ejemplo, The Transgenic Drosophila Facility en Michigan State University, The Transgenic Zebrafish Core Facility en el Medical College of Georgia (Augusta, Georgia) y Xenogen Biosciences (St. Louis, MO). En general, la construcción que contiene el transgén se suministra a la instalación para generar un animal transgénico.
Los procedimientos para generar animales transgénicos incluyen la introducción del transgén en la línea germinal del animal. Un método consiste en la microinyección de un constructo genético en el pronúcleo de un embrión de etapa temprana (por ejemplo, antes de la etapa de cuatro células, Wagner et al., 1981, Proc. Nat. Acad. Sci. USA
78: 5016, Brinster et al. 1985, Proc. Nat. Acad. Sci. USA 82: 4438). AlteARNtivamente, el transgén puede introducirse en el pronúcleo por infección retroviral. Se ha descrito un procedimiento detallado para producir tales ratones transgénicos (véase, por ejemplo, Hogan et al., Manipulating the Embryo Mouse, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1986), Patente U.S. nº 5.175.383 (1992)). Este procedimiento también se ha adaptado para otras especies animales (por ejemplo, Hammer et al., 1985, Nature 315: 680, Murray et al., 1989, Reprod. Fert. Dev 1: 147, Pursel et al., 1987, Vet Rexroad et al., 1990, J. Reprod. Fert. 41 (suppl): 119, Rexroad et al., 1989, Molec. Reprod. Dev.1: 164, Simons et al., 1988, BioTechnology 6: 179, Vize et al., 1988, J. Cell. Sci. 90: 295 y Wagner, 1989, J. Cell. Biochem., 13B (suppl): 164).
En resumen, el procedimiento implica la introducción del transgén en un animal mediante la microinyección de la construcción en los pronúcleos del huevo o mamíferos fecundados para hacer que una o más copias del transgén sean retenidas en las células del mamífero en desarrollo. Después de la introducción de la construcción transgénica en el huevo fertilizado, el óvulo puede incubarse in vitro durante cantidades variables de tiempo, o reimplantarse en un huésped sustituto, o ambos. Un método común es incubar los embriones in vitro durante aproximadamente 1-7 días, dependiendo de la especie, y luego reimplantarlos en el huésped sustituto. La presencia del transgén en la progenie de los embriones transgénicamente manipulados puede ser probada por análisis de transferencia Southern de un segmento de tejido.
Otro método para producir animales transgénicos de línea germinal es a través del uso de células de tallo embrionario (ES). La construcción génica puede introducirse en células madre embrionarias mediante recombinación homóloga (Thomas et al., 1987, Cell 51: 503, Capecchi, Science 1989, 244: 1288, Joyner et al., 1989, Nature 338: 153) en una región transcripcionalmente activa del genoma. Una construcción adecuada también se puede introducir en células madre embrionarias mediante transfección mediada por ADN, tal como por electroporación (Ausubel y col., Current Protocols in Molecular Biology, John Wiley & Sons, 1987). Los procedimientos detallados para cultivar células madre embrionarias (por ejemplo, ES-D3, ATCC # CCL-1934, ES-E14TG2a, ATCC # CCL-1821, American Type Culture Collection, Rockville, MD) y métodos para producir animales
9
5
10
15
20
25
30
35
40
45
50
55
60
naturaleza similar: un aglutinante tal como celulosa microcristalina, goma de tragacanto o gelatina; un excipiente tal como almidón o lactosa, un agente desintegrante tal como ácido algínico, Primogel™, o almidón de maíz; un lubricante tal como estearato de magnesio o SterotesTM; un deslizante tal como dióxido de silicio coloidal; un agente edulcorante tal como sacarosa o sacarina; o un agente aromatizante tal como menta, salicilato de metilo o aroma de naranja.
Para la administración por inhalación, los compuestos se suministran en forma de una pulverización de aerosol a partir de un recipiente o dispensador a presión que contiene un propulsor adecuado, por ejemplo, un gas tal como dióxido de carbono o un nebulizador.
La administración sistémica también puede ser por medios transmucosa o transdérmicos. Para la administración transmucosa o transdérmica, se utilizan en la formulación agentes de penetración apropiados para la barrera que se va a permear. Tales agentes de penetración son generalmente conocidos en la técnica, e incluyen, por ejemplo, para administración transmucosa, detergentes, sales biliares y derivados de ácido fusídico. La administración transmucosa puede lograrse mediante el uso de aerosoles nasales o supositorios. Para la administración transdérmica, los compuestos activos se formulan en ungüentos, bálsamos, geles o cremas, como se conoce generalmente en la técnica.
Los compuestos también pueden prepararse en forma de supositorios (por ejemplo, con bases de supositorios convencionales tales como manteca de cacao y otros glicéridos) o enemas de retención para administración rectal.
En una realización, los compuestos activos se preparan con vehículos que protegerán el compuesto contra la eliminación rápida del cuerpo, tal como una formulación de liberación controlada, que incluye implantes y sistemas de administración microencapsulados. Pueden usarse polímeros biodegradables, biocompatibles, tales como etilenacetato de vinilo, polianhídridos, ácido poliglicólico, colágeno, poliortoésteres y ácido poliláctico. Los métodos para la preparación de tales formulaciones serán evidentes para los expertos en la técnica. Los materiales también se pueden obtener comercialmente de Alza Corporation y Nova Pharmaceuticals, Inc. Las suspensiones liposómicas (incluyendo liposomas dirigidos a células infectadas con anticuerpos monoclonales contra antígenos virales) también pueden usarse como vehículos farmacéuticamente aceptables. Estos pueden prepararse de acuerdo con métodos conocidos por los expertos en la técnica, por ejemplo, como se describe en la Patente de Estados Unidos Nº
4.522.811.
Es ventajoso formular composiciones orales o parenterales en forma de unidad de dosificación para facilidad de administración y uniformidad de dosificación. La forma de unidad de dosificación tal como se utiliza en el presente documento se refiere a unidades físicamente discretas adecuadas como dosis unitarias para el sujeto que se va a tratar; conteniendo cada unidad una cantidad predeterminada de compuesto activo calculada para producir el efecto terapéutico deseado en asociación con el vehículo farmacéutico requerido.
La toxicidad y la eficacia terapéutica de tales compuestos se pueden determinar por procedimientos farmacéuticos estándar en cultivos celulares o animales de experimentación, por ejemplo, para determinar la DL50 (la dosis letal para el 50% de la población) y la ED50 (la dosis terapéuticamente efectiva en el 50% de la población). La relación de dosis entre los efectos tóxicos y terapéuticos es el índice terapéutico y puede expresarse como la relación DL50/ED50. Se prefieren los compuestos que exhiben altos índices terapéuticos. Aunque pueden utilizarse compuestos que exhiben efectos secundarios tóxicos, se debe tener cuidado de diseñar un sistema de liberación que dirija dichos compuestos al sitio del tejido afectado con el fin de minimizar el daño potencial a células no infectadas y, por tanto, reducir los efectos secundarios.
Los datos obtenidos a partir de ensayos de cultivos celulares y estudios en animales se pueden usar en la formulación de una gama de dosis para su uso en seres humanos. La dosificación de composiciones está preferiblemente dentro de un intervalo de concentraciones circulantes que incluyen un ED50 con poca o ninguna toxicidad. La dosificación puede variar dentro de este intervalo dependiendo de la forma de dosificación empleada y de la ruta de administración utilizada. Para cualquier compuesto, la dosis terapéuticamente eficaz se puede estimar inicialmente a partir de ensayos de cultivo celular. Se puede formular una dosis en modelos animales para conseguir un intervalo de concentración en plasma circulante del compuesto o, cuando sea apropiado, del producto polipeptídico de una secuencia diana (por ejemplo, lograr una concentración disminuida del polipéptido) que incluye la CI50 (es decir, la concentración del compuesto de ensayo que logra una inhibición semimáxima de los síntomas) determinada en cultivo celular. Tal información puede usarse para determinar con mayor precisión dosis útiles en humanos. Los niveles en el plasma se pueden medir, por ejemplo, mediante cromatografía líquida de alto rendimiento.
Una cantidad terapéuticamente eficaz de una composición que contiene una secuencia que codifica un precursor de ARN manipulado, o el propio precursor (es decir, una dosificación eficaz), es una cantidad que inhibe la expresión del polipéptido codificado por el gen diana en al menos 30 por ciento. Los porcentajes más altos de inhibición, por ejemplo , 45, 50, 75, 85, 90 por ciento o más pueden ser preferidos en ciertas realizaciones. Las dosis de ejemplo incluyen cantidades en miligramos o microgramos de la molécula por kilogramo de peso del sujeto o muestra (por ejemplo, aproximadamente 1 microgramo por kilogramo a aproximadamente 500 miligramos por kilogramo, aproximadamente 100 microgramos por kilogramo a aproximadamente 5 miligramos por kilogramo, o aproximadamente 1 microgramo por kilogramo a aproximadamente 50 microgramos por kilogramo. Las
14
5
10
15
20
25
30
35
40
45
Ejemplos de trastornos que implican el corazón o "trastorno cardiovascular" incluyen, pero no se limitan a, una enfermedad, un trastorno o un estado que implican el sistema cardiovascular, por ejemplo, el corazón, los vasos sanguíneos, y/o la sangre. Un trastorno cardiovascular puede ser causado por un desequilibrio en la presión arterial, un mal funcionamiento del corazón, o una oclusión de un vaso sanguíneo, por ejemplo, por un trombo. Ejemplos de tales trastornos incluyen la hipertensión, la aterosclerosis, espasmo de la arteria coronaria, insuficiencia cardíaca congestiva, enfermedad arterial coronaria, enfermedad valvular, arritmias, y cardiomiopatías.
Trastornos que pueden tratarse por los métodos descritos en este documento incluyen, pero no se limitan a, trastornos asociados con una acumulación en el hígado de tejido fibroso, como la que resulta de un desequilibrio entre la producción y degradación de la matriz extracelular acompañado por el colapso y condensación de fibras preexistentes.
Además, las moléculas de la invención pueden usarse para tratar enfermedades virales, incluyendo pero sin limitarse a hepatitis B, hepatitis C, virus del herpes simple (HSV), VIH-SIDA, virus del polio y virus de la viruela. Las moléculas de la invención se diseñan como se describe en la presente memoria descriptiva para dirigir secuencias expresadas de un virus, mejorando así la actividad viral y la replicación. Las moléculas pueden usarse en el tratamiento y/o diagnóstico de tejido infectado por virus. También, tales moléculas pueden usarse en el tratamiento de carcinoma asociado a un virus, tal como cáncer hepatocelular.
Usos de precursores de ARN manipulados para inducir ARNi
Los precursores de ARN manipulados, introducidos en células u organismos enteros como se describen aquí, darán lugar a la producción de una molécula de ARNsi deseada. Tal molécula de ARNsi se asociará entonces con componentes de proteínas endógenas de la ruta ARNi para unirse a una secuencia de ARNm específica y segmentarla para la escisión y la destrucción. De esta manera, el ARNm a ser dirigido por el ARNsi generado a partir del precursor de ARN manipulado será empobrecido de la célula u organismo, dando lugar a una disminución en la concentración de la proteína codificada por ese ARNm en la célula u organismo.
Por ejemplo, se puede estar tratando de descubrir una molécula pequeña que reduzca la actividad de una quinasa cuya sobreexpresión conduce a una proliferación celular desenfrenada. Esta quinasa se sobreexpresa en una variedad de células cancerosas. Una pregunta clave a determinar es si la disminución de la actividad de esta quinasa en mamíferos adultos tendría efectos deletéreos inesperados. Mediante la expresión de un precursor de ARN manipulado que se dirige a la destrucción por la ruta ARNi, el ARNm que codifica la quinasa a través de los tejidos de un ratón adulto, se pueden determinar los efectos deletéreos de dicho fármaco potencial. Es decir, el método descrito aquí permitirá una evaluación rápida de la idoneidad de la quinasa como un objetivo de fármaco.
Las nuevas moléculas de ácido nucleico que codifican los precursores de ARN manipulados también pueden usarse para crear un gran número de células o vectores en microarreglos en los que cada célula o vector de la matriz incluye moléculas de ácido nucleico que codifican un precursor de ARN manipulado que es específico Para un gen diana diferente. Véase, por ejemplo, Ziauddin et al., Nature, 411: 107 -110 (2001).
Ejemplos
La invención se describe adicionalmente en los siguientes ejemplos, los cuales no limitan el alcance de la invención descrita en las reivindicaciones.
Ejemplo 1 -Producción de un precursor de ARN manipulados
Para producir un precursor de ARN manipulado que se dirigirá a un gen para luciferasa de luciéARNga para escisión, se examinó la secuencia de la porción codificante del ARNm de luciferasa de luciéARNga para seleccionar una secuencia adecuada. En una posición de más de 100 nucleótidos, pero menos de 300 nucleótidos, 3’ al comienzo de la traducción, se encontró inmediatamente la secuencia CGUACGCGGAAUACUUCGAUU (SEQ ID NO: 16) después de la secuencia AA. Se eligió esta secuencia dado que cumple los criterios para la selección de un ARNsi,. Se diseñó entonces un ARN precursor modificado que incluye esta secuencia (subrayada) como se representa a continuación (y se muestra en la Figura 2B):
Se prepararon secuencias sintéticas de desoxioligonucleótidos que sirven como una plantilla de transcripción in vitro para preparar este precursor de ARN manipulado usando la enzima ARN Polimerasa T7 de acuerdo con los protocolos publicados. A continuación se muestran los dos desoxioligonucleótidos. Los oligonucleótidos contienen la
17
Claims (1)
-
imagen1 imagen2 imagen3
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US30518501P | 2001-07-12 | 2001-07-12 | |
US305185P | 2001-07-12 |
Publications (1)
Publication Number | Publication Date |
---|---|
ES2609014T3 true ES2609014T3 (es) | 2017-04-18 |
Family
ID=23179696
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES10183024.8T Expired - Lifetime ES2609014T3 (es) | 2001-07-12 | 2002-07-12 | Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico |
ES02746979.0T Expired - Lifetime ES2566561T3 (es) | 2001-07-12 | 2002-07-12 | Producción in vivo de ARN pequeños de interferencia que median el silenciamiento génico |
ES07023866.2T Expired - Lifetime ES2606290T3 (es) | 2001-07-12 | 2002-07-12 | Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES02746979.0T Expired - Lifetime ES2566561T3 (es) | 2001-07-12 | 2002-07-12 | Producción in vivo de ARN pequeños de interferencia que median el silenciamiento génico |
ES07023866.2T Expired - Lifetime ES2606290T3 (es) | 2001-07-12 | 2002-07-12 | Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico |
Country Status (9)
Country | Link |
---|---|
US (8) | US7691995B2 (es) |
EP (3) | EP2345720A3 (es) |
JP (1) | JP4210737B2 (es) |
KR (2) | KR101021695B1 (es) |
BR (1) | BR0211111A (es) |
CA (2) | CA2921821A1 (es) |
ES (3) | ES2609014T3 (es) |
IL (3) | IL159756A0 (es) |
WO (1) | WO2003006477A1 (es) |
Families Citing this family (199)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AUPP249298A0 (en) | 1998-03-20 | 1998-04-23 | Ag-Gene Australia Limited | Synthetic genes and genetic constructs comprising same I |
EP1555317B1 (en) | 1998-03-20 | 2011-09-28 | Commonwealth Scientific And Industrial Research Organisation | Synthetic genes and genetic constructs comprising the same |
CA2361201A1 (en) | 1999-01-28 | 2000-08-03 | Medical College Of Georgia Research Institute, Inc. | Composition and method for in vivo and in vitro attenuation of gene expression using double stranded rna |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
US6423885B1 (en) | 1999-08-13 | 2002-07-23 | Commonwealth Scientific And Industrial Research Organization (Csiro) | Methods for obtaining modified phenotypes in plant cells |
US7829693B2 (en) | 1999-11-24 | 2010-11-09 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
JP2003526367A (ja) * | 2000-03-16 | 2003-09-09 | ジェネティカ インコーポレイテッド | Rna干渉の方法とrna干渉組成物 |
US8202846B2 (en) | 2000-03-16 | 2012-06-19 | Cold Spring Harbor Laboratory | Methods and compositions for RNA interference |
US8546143B2 (en) | 2001-01-09 | 2013-10-01 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of a target gene |
US7767802B2 (en) | 2001-01-09 | 2010-08-03 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting expression of anti-apoptotic genes |
US20020132257A1 (en) | 2001-01-31 | 2002-09-19 | Tony Giordano | Use of post-transcriptional gene silencing for identifying nucleic acid sequences that modulate the function of a cell |
JP4210737B2 (ja) * | 2001-07-12 | 2009-01-21 | ユニバーシティー オブ マサチューセッツ | 遺伝子サイレンシングを仲介する低分子干渉リボ核酸のインビボにおける製造方法 |
DK2280070T3 (en) | 2001-07-23 | 2015-08-24 | Univ Leland Stanford Junior | Methods and compositions for use in RNAi-mediated inhibition of gene expression in mammals |
US10590418B2 (en) | 2001-07-23 | 2020-03-17 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for RNAi mediated inhibition of gene expression in mammals |
DE10163098B4 (de) | 2001-10-12 | 2005-06-02 | Alnylam Europe Ag | Verfahren zur Hemmung der Replikation von Viren |
US7745418B2 (en) | 2001-10-12 | 2010-06-29 | Alnylam Pharmaceuticals, Inc. | Compositions and methods for inhibiting viral replication |
WO2003046173A1 (fr) * | 2001-11-28 | 2003-06-05 | Center For Advanced Science And Technology Incubation, Ltd. | Systeme d'expression d'arn si et procede de production de cellules d'inactivation de genes fonctionnelles et analogues au moyen de ce systeme |
GB0130955D0 (en) | 2001-12-24 | 2002-02-13 | Cancer Res Ventures | Expression system |
DE10202419A1 (de) | 2002-01-22 | 2003-08-07 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines durch eine Chromosomen-Aberration entstandenen Zielgens |
CA2476530A1 (en) | 2002-02-14 | 2003-08-21 | City Of Hope | Methods for producing interfering rna molecules in mammalian cells and therapeutic uses for such molecules |
WO2003093441A2 (en) | 2002-05-03 | 2003-11-13 | Duke University | A method of regulating gene expression |
US20040241854A1 (en) | 2002-08-05 | 2004-12-02 | Davidson Beverly L. | siRNA-mediated gene silencing |
US20050106731A1 (en) * | 2002-08-05 | 2005-05-19 | Davidson Beverly L. | siRNA-mediated gene silencing with viral vectors |
US20080274989A1 (en) | 2002-08-05 | 2008-11-06 | University Of Iowa Research Foundation | Rna Interference Suppression of Neurodegenerative Diseases and Methods of Use Thereof |
US20040023390A1 (en) * | 2002-08-05 | 2004-02-05 | Davidson Beverly L. | SiRNA-mediated gene silencing with viral vectors |
US20050042646A1 (en) | 2002-08-05 | 2005-02-24 | Davidson Beverly L. | RNA interference suppresion of neurodegenerative diseases and methods of use thereof |
WO2004014933A1 (en) | 2002-08-07 | 2004-02-19 | University Of Massachusetts | Compositions for rna interference and methods of use thereof |
AU2002951347A0 (en) * | 2002-09-09 | 2002-09-26 | Benitec Australia Ltd | Genetic silencing |
US9453251B2 (en) | 2002-10-08 | 2016-09-27 | Pfenex Inc. | Expression of mammalian proteins in Pseudomonas fluorescens |
US7892793B2 (en) * | 2002-11-04 | 2011-02-22 | University Of Massachusetts | Allele-specific RNA interference |
US20040191905A1 (en) * | 2002-11-22 | 2004-09-30 | University Of Massachusetts | Modulation of HIV replication by RNA interference |
US20060257851A1 (en) * | 2002-11-26 | 2006-11-16 | Itzhak Bentwich | Bioinformatically detectable group of novel viral regulatory genes and uses thereof |
ES2216707B1 (es) * | 2003-04-08 | 2005-12-16 | Josep Maria Aran Perramon | Secuencia oligoribonucleotidica homologa a una region del cdna que codifica para el receptor cd40 humano y oligoribonucleotidos duplex, vectores, composiciones farmaceuticas y usos correspondientes. |
US8609830B2 (en) | 2003-05-16 | 2013-12-17 | Merck Sharp & Dohme Corp. | Methods and compositions for RNA interference |
US20060178327A1 (en) * | 2003-05-30 | 2006-08-10 | Yeung Wah Hin A | Inhibition of gene expression by delivery of specially selected double stranded or other forms of small interfering RNA precursors enabling the formation and function of small interfering RNA in vivo and in vitro |
ES2357116T5 (es) * | 2003-06-02 | 2021-09-03 | Univ Massachusetts | Métodos y composiciones para mejorar la eficacia y especificad de FNAi |
US7750144B2 (en) | 2003-06-02 | 2010-07-06 | University Of Massachusetts | Methods and compositions for enhancing the efficacy and specificity of RNA silencing |
EP3502252B1 (en) * | 2003-06-02 | 2023-04-05 | University of Massachusetts | Methods and compositions for controlling efficacy of rna silencing |
SI2270162T1 (sl) | 2003-06-12 | 2019-03-29 | Alnylam Pharmaceuticals Inc. | Konzervirana HBV in HCV zaporedja uporabna za utišanje genov |
US8575327B2 (en) | 2003-06-12 | 2013-11-05 | Alnylam Pharmaceuticals, Inc. | Conserved HBV and HCV sequences useful for gene silencing |
US8106180B2 (en) * | 2003-08-07 | 2012-01-31 | Whitehead Institute For Biomedical Research | Methods and products for expression of micro RNAs |
US8680063B2 (en) | 2003-09-12 | 2014-03-25 | University Of Massachusetts | RNA interference for the treatment of gain-of-function disorders |
EP2821085B1 (en) * | 2003-09-12 | 2020-04-29 | University of Massachusetts | Rna interference for the treatment of gain-of-function disorders |
US7480382B2 (en) * | 2003-09-30 | 2009-01-20 | Microsoft Corporation | Image file container |
US20050120415A1 (en) | 2003-10-09 | 2005-06-02 | E.I. Du Pont De Nemours And Company | Gene silencing |
JP4777251B2 (ja) | 2003-10-14 | 2011-09-21 | バクスター・インターナショナル・インコーポレイテッド | ビタミンkエポキシド還元酵素複合体サブユニット1vkorc1、クマリンおよびその誘導体の治療標的 |
EP1694838A2 (en) * | 2003-10-23 | 2006-08-30 | Sirna Therapeutics, Inc. | RNA INTERFERENCE MEDIATED INHIBITION OF GPRA AND AAA1 GENE EXPRESSION USING SHORT NUCLEIC ACID (siNA) |
WO2005042708A2 (en) | 2003-10-27 | 2005-05-12 | Rosetta Inpharmatics Llc | METHOD OF DESIGNING siRNAS FOR GENE SILENCING |
CN1972593A (zh) | 2003-11-21 | 2007-05-30 | 雷维维科公司 | 干扰rna在生产转基因动物中的用途 |
US20060134787A1 (en) | 2004-12-22 | 2006-06-22 | University Of Massachusetts | Methods and compositions for enhancing the efficacy and specificity of single and double blunt-ended siRNA |
WO2005079533A2 (en) * | 2004-02-17 | 2005-09-01 | University Of Massachusetts | Methods and compositions for mediating gene silencing |
US20050273868A1 (en) * | 2004-02-17 | 2005-12-08 | University Of Massachusetts | Methods and compositions for enhancing RISC activity in vitro and in vivo |
US8084599B2 (en) | 2004-03-15 | 2011-12-27 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
US20070265220A1 (en) | 2004-03-15 | 2007-11-15 | City Of Hope | Methods and compositions for the specific inhibition of gene expression by double-stranded RNA |
EP2412816B1 (en) | 2004-07-26 | 2014-12-03 | Pfenex Inc. | Process for improved protein expression by strain engineering |
US20060046248A1 (en) * | 2004-08-25 | 2006-03-02 | Avigenics, Inc. | RNA interference in avians |
AU2005276144B2 (en) | 2004-08-26 | 2010-08-05 | The University Of Western Ontario | Pharmaceutical compositions comprising inhibitors of iron transport, and method of identifying iron transport inhibitors, FN Staphylococcus aureus |
EP1809748B1 (en) * | 2004-10-12 | 2012-12-26 | The Rockefeller University | Micrornas |
EP1812596A4 (en) * | 2004-10-12 | 2010-07-14 | Wayne John Cancer Inst | TREATMENT OF CANCER AND COMPOSITIONS |
CA2584960A1 (en) | 2004-10-21 | 2006-05-04 | Charles L. Niblett | Methods and materials for conferring resistance to pests and pathogens of plants |
WO2006081158A2 (en) * | 2005-01-25 | 2006-08-03 | The Regents Of The University Of California | Predictive and therapeutic markers in overian cancer |
EP1861499A4 (en) | 2005-03-15 | 2008-09-03 | Univ North Carolina | METHODS AND COMPOSITIONS FOR THE PRODUCTION OF ACTIVE PROTEINS DEPENDENT ON VITAMIN K |
KR100694804B1 (ko) | 2005-05-18 | 2007-03-14 | 아주대학교산학협력단 | 작은 헤어핀 rna 분자를 포함하는 자궁 내막암 치료또는 예방용 조성물 및 그를 이용한 자궁 내막암 치료 또는예방 방법 |
WO2007011702A2 (en) | 2005-07-15 | 2007-01-25 | The University Of North Carolina At Chapel Hill | Use of egfr inhibitors to prevent or treat obesity |
EP2239328A3 (en) * | 2005-08-18 | 2011-01-05 | Alnylam Pharmaceuticals Inc. | Methods and compositions for treating neurological disease |
EP2980220A1 (en) | 2005-09-20 | 2016-02-03 | BASF Plant Science GmbH | Improved methods controlling gene expression |
KR100877824B1 (ko) | 2005-11-11 | 2009-01-12 | 한국생명공학연구원 | E2epf ucp-vhl 상호작용 및 그 용도 |
US8916530B2 (en) | 2005-11-18 | 2014-12-23 | Gradalis, Inc. | Individualized cancer therapy |
US8603991B2 (en) | 2005-11-18 | 2013-12-10 | Gradalis, Inc. | Individualized cancer therapy |
WO2007087113A2 (en) | 2005-12-28 | 2007-08-02 | The Scripps Research Institute | Natural antisense and non-coding rna transcripts as drug targets |
US8758998B2 (en) | 2006-11-09 | 2014-06-24 | Gradalis, Inc. | Construction of bifunctional short hairpin RNA |
US8906874B2 (en) | 2006-11-09 | 2014-12-09 | Gradalis, Inc. | Bi-functional shRNA targeting Stathmin 1 and uses thereof |
US8252526B2 (en) | 2006-11-09 | 2012-08-28 | Gradalis, Inc. | ShRNA molecules and methods of use thereof |
CN101646769A (zh) | 2007-02-20 | 2010-02-10 | 孟山都技术公司 | 无脊椎动物微rna |
US9580719B2 (en) | 2007-04-27 | 2017-02-28 | Pfenex, Inc. | Method for rapidly screening microbial hosts to identify certain strains with improved yield and/or quality in the expression of heterologous proteins |
EP2142651B1 (en) | 2007-04-27 | 2013-05-22 | Pfenex Inc. | Method for rapidly screening microbial hosts to identify certain strains with improved yield and/or quality in the expression of heterologous proteins |
WO2008143774A2 (en) * | 2007-05-01 | 2008-11-27 | University Of Massachusetts | Methods and compositions for locating snp heterozygosity for allele specific diagnosis and therapy |
ES2573936T3 (es) | 2007-05-22 | 2016-06-13 | Arcturus Therapeutics, Inc. | Oligómeros para agentes terapéuticos |
CN101541963B (zh) * | 2007-05-25 | 2012-10-31 | 三得利控股株式会社 | 新型溶血磷脂酸酰基转移酶基因 |
CN101820757A (zh) | 2007-06-01 | 2010-09-01 | 普林斯顿大学托管委员会 | 通过调节宿主细胞代谢途径治疗病毒感染 |
JP5188107B2 (ja) * | 2007-06-21 | 2013-04-24 | 株式会社東芝 | アレイ型受光素子 |
US8183221B2 (en) * | 2007-09-05 | 2012-05-22 | Medtronic, Inc. | Suppression of SCN9A gene expression and/or function for the treatment of pain |
WO2010033225A2 (en) * | 2008-09-22 | 2010-03-25 | Dicerna Pharmaceuticals, Inc. | Compositions and methods for the specific inhibition of gene expression by dsrna possessing modifications |
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 |
ES2526868T3 (es) | 2008-10-14 | 2015-01-16 | Invista Technologies S.À.R.L. | Procedimiento de preparación de 2-alquilsecundario-4,5-di-(alquilnormal)fenoles |
JP5816556B2 (ja) | 2008-12-03 | 2015-11-18 | アークトゥラス・セラピューティクス・インコーポレイテッドArcturus Therapeutics,Inc. | 治療剤のためのunaオリゴマー構造 |
KR101829469B1 (ko) * | 2008-12-04 | 2018-03-30 | 큐알엔에이, 인크. | Epo에 대한 천연 안티센스 전사체의 억제에 의해 에리트로포에틴(epo) 관련된 질환의 치료 |
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 |
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 |
CA3151965A1 (en) * | 2008-12-18 | 2010-07-15 | Dicerna Pharmaceuticals, Inc. | Extended dicer substrate agents and methods for the specific inhibition of gene expression |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
KR101548567B1 (ko) | 2009-12-23 | 2015-09-01 | 그래댈리스, 인코포레이티드 | 푸린―녹다운 및 gm―csf―증강된 (fang) 암 백신 |
SG181881A1 (en) | 2009-12-23 | 2012-07-30 | Gradalis Inc | Furin-knockdown bi-functional rna |
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 |
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 |
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 |
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 |
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 |
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 |
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) |
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 |
MX343604B (es) * | 2010-05-28 | 2016-11-11 | Genentech Inc | Disminuir nivel de lactato e incrementar producción de polipéptidos por regulación a la baja de la expresión de lactato dehidrogenasa y piruvato dehidrogenasa quinasa. |
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 |
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 |
US20120083035A1 (en) | 2010-09-30 | 2012-04-05 | Dharmacon, Inc. | Modified Cell Lines for Increasing Lentiviral Titers |
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 |
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 |
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 |
WO2012088222A2 (en) | 2010-12-21 | 2012-06-28 | The University Of North Carolina At Chapel Hill | Methods and compositions for producing active vitamin k-dependent proteins |
KR20200023495A (ko) | 2011-01-10 | 2020-03-04 | 더 리젠츠 오브 더 유니버시티 오브 미시간 | 줄기 세포 인자 억제제 |
RU2620980C2 (ru) | 2011-06-09 | 2017-05-30 | Курна, Инк. | Лечение заболеваний, связанных с фратаксином (fxn), путем ингибирования природного антисмыслового транскрипта fxn |
WO2013001372A2 (en) | 2011-06-30 | 2013-01-03 | University Of Oslo | Methods and compositions for inhibition of activation of regulatory t cells |
RS55088B1 (sr) | 2011-07-06 | 2016-12-30 | Sykehuset Sorlandet Hf | Egfr ciljana terapija |
EA029151B1 (ru) | 2011-09-06 | 2018-02-28 | Курна, Инк. | ЛЕЧЕНИЕ ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АЛЬФА-СУБЪЕДИНИЦАМИ ПОТЕНЦИАЛЗАВИСИМЫХ НАТРИЕВЫХ КАНАЛОВ (SCNxA), С ПОМОЩЬЮ МАЛЫХ МОЛЕКУЛ |
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 |
GEP20217251B (en) | 2012-05-25 | 2021-04-26 | Charpentier Emmanuelle De Emanuel | Methods and compositions for rna-directed target dna modification and for rna-directed modulation of transcription |
EP2855684A1 (en) * | 2012-05-25 | 2015-04-08 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Vector for the selective silencing of a gene in astrocytes |
KR102676910B1 (ko) | 2012-12-06 | 2024-06-19 | 시그마-알드리치 컴퍼니., 엘엘씨 | Crispr-기초된 유전체 변형과 조절 |
EP2931892B1 (en) | 2012-12-12 | 2018-09-12 | The Broad Institute, Inc. | Methods, models, systems, and apparatus for identifying target sequences for cas enzymes or crispr-cas systems for target sequences and conveying results thereof |
MX2015007550A (es) | 2012-12-12 | 2017-02-02 | Broad Inst Inc | Suministro, modificación y optimización de sistemas, métodos y composiciones para la manipulación de secuencias y aplicaciones terapéuticas. |
US20150320861A1 (en) | 2012-12-21 | 2015-11-12 | Sykehuset Sørlandet Hf | Egfr targeted therapy of neurological disorders and pain |
WO2014204725A1 (en) | 2013-06-17 | 2014-12-24 | The Broad Institute Inc. | Optimized crispr-cas double nickase systems, methods and compositions for sequence manipulation |
DK3011029T3 (da) | 2013-06-17 | 2020-03-16 | Broad Inst Inc | Administration, modificering og optimering af tandem-guidesystemer, fremgangsmåder og sammensætninger til sekvensmanipulering |
DK3011031T3 (da) | 2013-06-17 | 2020-12-21 | Broad Inst Inc | Fremføring og anvendelse af crispr-cas-systemerne, vektorer og sammensætninger til levermålretning og -terapi |
AU2014281031B2 (en) | 2013-06-17 | 2020-05-21 | Massachusetts Institute Of Technology | Delivery, use and therapeutic applications of the CRISPR-Cas systems and compositions for targeting disorders and diseases using viral components |
WO2014204727A1 (en) | 2013-06-17 | 2014-12-24 | The Broad Institute Inc. | Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof |
WO2015006554A1 (en) | 2013-07-10 | 2015-01-15 | The Regents Of The University Of Michigan | Therapeutic antibodies and uses thereof |
EP3079725B1 (en) | 2013-12-12 | 2019-10-16 | The Broad Institute, Inc. | Delivery, use and therapeutic applications of the crispr-cas systems and compositions for genome editing |
WO2015089364A1 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Crystal structure of a crispr-cas system, and uses thereof |
EP3080257A1 (en) | 2013-12-12 | 2016-10-19 | The Broad Institute Inc. | Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders |
WO2015089486A2 (en) | 2013-12-12 | 2015-06-18 | The Broad Institute Inc. | Systems, methods and compositions for sequence manipulation with optimized functional crispr-cas systems |
JP6681837B2 (ja) | 2014-03-11 | 2020-04-15 | セレクティスCellectis | 同種移植に適合するt細胞を作製するための方法 |
JP6756700B2 (ja) | 2014-03-18 | 2020-09-16 | ユニバーシティ オブ マサチューセッツ | 筋萎縮性側索硬化症を処置するためのrAAVベースの組成物および方法 |
WO2015148582A1 (en) | 2014-03-25 | 2015-10-01 | Arcturus Therapeutics, Inc. | Transthyretin allele selective una oligomers for gene silencing |
US9856475B2 (en) | 2014-03-25 | 2018-01-02 | Arcturus Therapeutics, Inc. | Formulations for treating amyloidosis |
WO2015148580A2 (en) | 2014-03-25 | 2015-10-01 | Arcturus Therapeutics, Inc. | Una oligomers having reduced off-target effects in gene silencing |
EP4299126A3 (en) | 2014-06-26 | 2024-04-03 | The Johns Hopkins University | Peripherally restricted gaba positive allosteric modulators for the treatment of irritable bowel syndrome and other ailments of the peripheral nervous system |
JOP20200092A1 (ar) | 2014-11-10 | 2017-06-16 | Alnylam Pharmaceuticals Inc | تركيبات iRNA لفيروس الكبد B (HBV) وطرق لاستخدامها |
KR102599909B1 (ko) | 2014-11-14 | 2023-11-09 | 보이저 테라퓨틱스, 인크. | 근위축성 측삭 경화증(als)을 치료하는 조성물 및 방법 |
WO2016094867A1 (en) | 2014-12-12 | 2016-06-16 | The Broad Institute Inc. | Protected guide rnas (pgrnas) |
WO2016161299A1 (en) | 2015-04-01 | 2016-10-06 | Arcturus Therapeutics, Inc. | Therapeutic una oligomers and uses thereof |
TW202400626A (zh) | 2015-06-18 | 2024-01-01 | 美商博得學院股份有限公司 | 降低脫靶效應的crispr酶突變 |
WO2016205759A1 (en) | 2015-06-18 | 2016-12-22 | The Broad Institute Inc. | Engineering and optimization of systems, methods, enzymes and guide scaffolds of cas9 orthologs and variants for sequence manipulation |
WO2017015671A1 (en) | 2015-07-23 | 2017-01-26 | Arcturus Therapeutics, Inc. | Compositions for treating amyloidosis |
EP3386544B1 (en) | 2015-12-10 | 2020-11-25 | Fibrogen, Inc. | Methods for treatment of motor neuron diseases |
KR101965379B1 (ko) * | 2016-04-29 | 2019-04-03 | 이화여자대학교 산학협력단 | 유전자 침묵효과가 강화된 다이서 기질로서의 rna 나노구조체 및 이의 제조 방법 |
SG11201809643UA (en) | 2016-05-18 | 2018-12-28 | Voyager Therapeutics Inc | Compositions and methods of treating huntington's disease |
IL302748A (en) | 2016-05-18 | 2023-07-01 | Voyager Therapeutics Inc | modulatory polynucleotides |
US20190367930A1 (en) | 2016-07-29 | 2019-12-05 | Danmarks Tekniske Universitet | Methods for decoupling cell growth from production of biochemicals and recombinant polypeptides |
US10457940B2 (en) * | 2016-09-22 | 2019-10-29 | University Of Massachusetts | AAV treatment of Huntington's disease |
AU2017377661B2 (en) * | 2016-12-14 | 2023-07-27 | Benitec IP Holdings Inc. | Reagents for treatment of oculopharyngeal muscular dystrophy (opmd) and use thereof |
EP3573448A4 (en) | 2017-01-28 | 2020-09-02 | Inari Agriculture, Inc. | NEW PLANT CELLS, PLANTS AND SEEDS |
EP3580339A4 (en) * | 2017-02-10 | 2020-12-23 | Research & Business Foundation Sungkyunkwan University | LONG DOUBLE STRAND RNA FOR RNA INTERFERENCE |
US11324820B2 (en) | 2017-04-18 | 2022-05-10 | Alnylam Pharmaceuticals, Inc. | Methods for the treatment of subjects having a hepatitis b virus (HBV) infection |
WO2018204786A1 (en) | 2017-05-05 | 2018-11-08 | Voyager Therapeutics, Inc. | Compositions and methods of treating amyotrophic lateral sclerosis (als) |
MX2019013172A (es) | 2017-05-05 | 2020-09-07 | Voyager Therapeutics Inc | Composiciones y metodos para tratar la enfermedad de huntington. |
AU2018264996A1 (en) | 2017-05-09 | 2019-12-05 | University Of Massachusetts | Methods of treating Amyotrophic Lateral Sclerosis (ALS) |
CN111448321A (zh) | 2017-09-22 | 2020-07-24 | 马萨诸塞大学 | Sod1双表达载体及其用途 |
US11603536B2 (en) | 2017-09-29 | 2023-03-14 | Inari Agriculture Technology, Inc. | Methods for efficient maize genome editing |
TWI804518B (zh) | 2017-10-16 | 2023-06-11 | 美商航海家醫療公司 | 肌萎縮性脊髓側索硬化症(als)之治療 |
EP3697908A1 (en) | 2017-10-16 | 2020-08-26 | Voyager Therapeutics, Inc. | Treatment of amyotrophic lateral sclerosis (als) |
US11926835B1 (en) | 2018-01-29 | 2024-03-12 | Inari Agriculture Technology, Inc. | Methods for efficient tomato genome editing |
US11220694B1 (en) | 2018-01-29 | 2022-01-11 | Inari Agriculture, Inc. | Rice cells and rice plants |
US11802288B1 (en) | 2018-01-29 | 2023-10-31 | Inari Agriculture Technology, Inc. | Methods for efficient soybean genome editing |
KR20200108315A (ko) | 2018-02-09 | 2020-09-17 | 제넨테크, 인크. | Tmem106b의 발현을 조절하기 위한 올리고뉴클레오티드 |
CN112424376A (zh) | 2018-05-07 | 2021-02-26 | 罗氏创新中心哥本哈根有限公司 | 使用大规模平行测序对lna寡核苷酸治疗药物进行质量控制 |
US11866719B1 (en) | 2018-06-04 | 2024-01-09 | Inari Agriculture Technology, Inc. | Heterologous integration of regulatory elements to alter gene expression in wheat cells and wheat plants |
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 |
US20200369759A1 (en) | 2019-05-23 | 2020-11-26 | Fibrogen, Inc. | Methods of treatment of muscular dystrophies |
EP4288440A1 (en) | 2021-02-02 | 2023-12-13 | The Johns Hopkins University | Peripherally restricted gaba positive allosteric modulators |
Family Cites Families (98)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3023787A1 (de) | 1980-06-25 | 1982-01-21 | Studiengesellschaft Kohle mbH, 4330 Mülheim | Verfahren zur erhoehung der inkorporation und der expression von genetischem material in die kerne von intakten zellen mit hilfe von liposomen |
US4522811A (en) | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
US5208149A (en) * | 1983-10-20 | 1993-05-04 | The Research Foundation Of State University Of New York | Nucleic acid constructs containing stable stem and loop structures |
US4980286A (en) | 1985-07-05 | 1990-12-25 | Whitehead Institute For Biomedical Research | In vivo introduction and expression of foreign genetic material in epithelial cells |
IL79289A (en) | 1985-07-05 | 1992-01-15 | Whitehead Biomedical Inst | Introduction and expression of foreign genetic material into keratinocytes using a recombinant retrovirus |
JP2627899B2 (ja) | 1987-08-19 | 1997-07-09 | 株式会社 ビタミン研究所 | 遺伝子封入リポソームの製法 |
US5175385A (en) | 1987-09-03 | 1992-12-29 | Ohio University/Edison Animal Biotechnolgy Center | Virus-resistant transgenic mice |
US5252726A (en) | 1987-09-04 | 1993-10-12 | Novo Nordisk A/S | Promoters for use in aspergillus |
WO1989002468A1 (en) | 1987-09-11 | 1989-03-23 | Whitehead Institute For Biomedical Research | Transduced fibroblasts and uses therefor |
ATE110108T1 (de) | 1987-12-11 | 1994-09-15 | Whitehead Biomedical Inst | Genetische modifizierung von endothelialen zellen. |
JP2917998B2 (ja) | 1988-02-05 | 1999-07-12 | ホワイトヘッド・インスティチュート・フォー・バイオメディカル・リサーチ | 修飾された肝細胞およびその用途 |
US5070020A (en) | 1988-05-09 | 1991-12-03 | Eli Lilly And Company | Recombinant dna expression vectors and dna compounds that encode deacetoxycephalosporin c synthetase |
US5175384A (en) | 1988-12-05 | 1992-12-29 | Genpharm International | Transgenic mice depleted in mature t-cells and methods for making transgenic mice |
US5175383A (en) | 1989-02-17 | 1992-12-29 | President And Fellows Of Harvard College | Animal model for benign prostatic disease |
US5328470A (en) | 1989-03-31 | 1994-07-12 | The Regents Of The University Of Michigan | Treatment of diseases by site-specific instillation of cells or site-specific transformation of cells and kits therefor |
DK0497875T3 (da) * | 1989-10-24 | 2000-07-03 | Gilead Sciences Inc | 2'-modificerede oligonukleotider |
ATE157012T1 (de) | 1989-11-03 | 1997-09-15 | Univ Vanderbilt | Verfahren zur in vivo-verabreichung von funktionsfähigen fremden genen |
US6946587B1 (en) | 1990-01-22 | 2005-09-20 | Dekalb Genetics Corporation | Method for preparing fertile transgenic corn plants |
US5204253A (en) | 1990-05-29 | 1993-04-20 | E. I. Du Pont De Nemours And Company | Method and apparatus for introducing biological substances into living cells |
AU659824B2 (en) | 1990-10-31 | 1995-06-01 | Cell Genesys, Inc. | Retroviral vectors useful for gene therapy |
WO1994008003A1 (en) * | 1991-06-14 | 1994-04-14 | Isis Pharmaceuticals, Inc. | ANTISENSE OLIGONUCLEOTIDE INHIBITION OF THE ras GENE |
US6117847A (en) * | 1992-03-16 | 2000-09-12 | Isis Pharmaceuticals, Inc. | Oligonucleotides for enhanced modulation of protein kinase C expression |
US5792751A (en) | 1992-04-13 | 1998-08-11 | Baylor College Of Medicine | Tranformation of cells associated with fluid spaces |
US5693535A (en) | 1992-05-14 | 1997-12-02 | Ribozyme Pharmaceuticals, Inc. | HIV targeted ribozymes |
CZ333294A3 (en) | 1992-07-02 | 1995-07-12 | Hybridon | Self-stabilized oligonucleotide and inhibition method of virus gene or pathogenic organism or cellular gene expression |
US5808036A (en) * | 1993-09-01 | 1998-09-15 | Research Corporation Technologies Inc. | Stem-loop oligonucleotides containing parallel and antiparallel binding domains |
US5624803A (en) * | 1993-10-14 | 1997-04-29 | The Regents Of The University Of California | In vivo oligonucleotide generator, and methods of testing the binding affinity of triplex forming oligonucleotides derived therefrom |
DE4421079C1 (de) * | 1994-06-16 | 1995-08-17 | Peter Dr Rer Nat Seibel | Chimäres Peptid-Nukleinsäure-Fragment, Verfahren zu seiner Herstellung und die Verwendung des Fragments zur zielgerichteten Nukleinsäureeinbringung in Zellorganellen und Zellen |
US6057153A (en) * | 1995-01-13 | 2000-05-02 | Yale University | Stabilized external guide sequences |
US5631146A (en) | 1995-01-19 | 1997-05-20 | The General Hospital Corporation | DNA aptamers and catalysts that bind adenosine or adenosine-5'-phosphates and methods for isolation thereof |
WO1996029097A1 (en) * | 1995-03-21 | 1996-09-26 | Research Corporation Technologies, Inc. | Stem-loop and circular oligonucleotides |
US5674683A (en) * | 1995-03-21 | 1997-10-07 | Research Corporation Technologies, Inc. | Stem-loop and circular oligonucleotides and method of using |
GB9517780D0 (en) | 1995-08-31 | 1995-11-01 | Roslin Inst Edinburgh | Biological manipulation |
GB9517779D0 (en) | 1995-08-31 | 1995-11-01 | Roslin Inst Edinburgh | Biological manipulation |
US5998203A (en) * | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
US6022863A (en) | 1996-05-21 | 2000-02-08 | Yale University | Regulation of gene expression |
US5898031A (en) * | 1996-06-06 | 1999-04-27 | Isis Pharmaceuticals, Inc. | Oligoribonucleotides for cleaving RNA |
ES2150832B1 (es) | 1996-06-12 | 2001-06-16 | Fichtel & Sachs Ag | Dispositivo de maniobra para la maniobra, en particular maniobra neumatica, de un embrague de friccion. |
US20030064945A1 (en) * | 1997-01-31 | 2003-04-03 | Saghir Akhtar | Enzymatic nucleic acid treatment of diseases or conditions related to levels of epidermal growth factor receptors |
GB9703146D0 (en) * | 1997-02-14 | 1997-04-02 | Innes John Centre Innov Ltd | Methods and means for gene silencing in transgenic plants |
GB9710475D0 (en) | 1997-05-21 | 1997-07-16 | Zeneca Ltd | Gene silencing |
US6183959B1 (en) * | 1997-07-03 | 2001-02-06 | Ribozyme Pharmaceuticals, Inc. | Method for target site selection and discovery |
EP2253639A1 (en) | 1997-09-12 | 2010-11-24 | Exiqon A/S | Bi- and tri-cyclic nucleoside, nucleotide and oligonucleoide analogues |
GB9720148D0 (en) | 1997-09-22 | 1997-11-26 | Innes John Centre Innov Ltd | Gene silencing materials and methods |
US6506559B1 (en) | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
EP1555317B1 (en) * | 1998-03-20 | 2011-09-28 | Commonwealth Scientific And Industrial Research Organisation | Synthetic genes and genetic constructs comprising the same |
AUPP249298A0 (en) * | 1998-03-20 | 1998-04-23 | Ag-Gene Australia Limited | Synthetic genes and genetic constructs comprising same I |
EP2267139B1 (en) | 1998-04-08 | 2017-03-22 | Commonwealth Scientific and Industrial Research Organisation | Methods and means for obtaining modified phenotypes |
AR020078A1 (es) | 1998-05-26 | 2002-04-10 | Syngenta Participations Ag | Metodo para alterar la expresion de un gen objetivo en una celula de planta |
US6413776B1 (en) | 1998-06-12 | 2002-07-02 | Galapagos Geonomics N.V. | High throughput screening of gene function using adenoviral libraries for functional genomics applications |
GB9827152D0 (en) | 1998-07-03 | 1999-02-03 | Devgen Nv | Characterisation of gene function using double stranded rna inhibition |
CA2340335A1 (en) | 1998-08-20 | 2000-03-02 | Cell Genesys, Inc. | Use of suppressor trna's to regulate cytotoxicity during the production of recombinant gene products |
IT1302708B1 (it) | 1998-10-20 | 2000-09-29 | Unifor Spa | Contenitore di immagazzinaggio con porta controbilanciata |
EP1050583A4 (en) | 1998-11-24 | 2005-02-02 | Hisamitsu Pharmaceutical Co | INHIBITORS OF HIV INFECTIONS |
US6939712B1 (en) * | 1998-12-29 | 2005-09-06 | Impedagen, Llc | Muting gene activity using a transgenic nucleic acid |
CA2361201A1 (en) * | 1999-01-28 | 2000-08-03 | Medical College Of Georgia Research Institute, Inc. | Composition and method for in vivo and in vitro attenuation of gene expression using double stranded rna |
DE19956568A1 (de) | 1999-01-30 | 2000-08-17 | Roland Kreutzer | Verfahren und Medikament zur Hemmung der Expression eines vorgegebenen Gens |
AU3369900A (en) | 1999-02-19 | 2000-09-04 | General Hospital Corporation, The | Gene silencing |
GB9904905D0 (en) | 1999-03-03 | 1999-04-28 | Oxford Biomedica Ltd | Cells |
FR2790757B1 (fr) | 1999-03-09 | 2003-08-01 | Bioalliance Pharma | Oligonucleotides contenant une sequence antisens stabilises par une structure secondaire et compositions pharmaceutiques les contenant. |
AU781598B2 (en) | 1999-04-21 | 2005-06-02 | Alnylam Pharmaceuticals, Inc. | Methods and compositions for inhibiting the function of polynucleotide sequences |
US6423885B1 (en) * | 1999-08-13 | 2002-07-23 | Commonwealth Scientific And Industrial Research Organization (Csiro) | Methods for obtaining modified phenotypes in plant cells |
WO2001012789A2 (en) * | 1999-08-18 | 2001-02-22 | Baylor College Of Medicine | APOLIPOPROTEIN B mRNA-SPECIFIC RIBOZYME |
GB9927444D0 (en) | 1999-11-19 | 2000-01-19 | Cancer Res Campaign Tech | Inhibiting gene expression |
DE10100586C1 (de) | 2001-01-09 | 2002-04-11 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines Ziegens |
DE10160151A1 (de) | 2001-01-09 | 2003-06-26 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines vorgegebenen Zielgens |
RU2164944C1 (ru) | 1999-12-09 | 2001-04-10 | Институт молекулярной биологии им. В.А. Энгельгардта РАН | Способ изменения генетических свойств организма |
US20050229272A1 (en) | 1999-12-30 | 2005-10-13 | Monica Driscoll | Compositions and methods for gene silencing |
US20030084471A1 (en) | 2000-03-16 | 2003-05-01 | David Beach | Methods and compositions for RNA interference |
JP2003526367A (ja) | 2000-03-16 | 2003-09-09 | ジェネティカ インコーポレイテッド | Rna干渉の方法とrna干渉組成物 |
US8202846B2 (en) | 2000-03-16 | 2012-06-19 | Cold Spring Harbor Laboratory | Methods and compositions for RNA interference |
WO2001070949A1 (en) * | 2000-03-17 | 2001-09-27 | Benitec Australia Ltd | Genetic silencing |
KR20080023768A (ko) | 2000-03-30 | 2008-03-14 | 화이트헤드 인스티튜트 포 바이오메디칼 리서치 | Rna 간섭의 rna 서열 특이적인 매개체 |
US6506099B1 (en) | 2000-04-05 | 2003-01-14 | Applied Materials, Inc. | Driving a carrier head in a wafer polishing system |
US20100305186A1 (en) | 2000-05-30 | 2010-12-02 | Johnson & Johnson Research Pty Limited | Methods for mediating gene suppression |
CZ302719B6 (cs) | 2000-12-01 | 2011-09-21 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Izolovaná molekula dvouretezcové RNA, zpusob její výroby a její použití |
AU2002248173B2 (en) | 2000-12-08 | 2007-04-26 | Invitrogen Corporation | Compositions and methods for rapidly generating recombinant nucleic acid molecules |
US20020160393A1 (en) | 2000-12-28 | 2002-10-31 | Symonds Geoffrey P. | Double-stranded RNA-mediated gene suppression |
US20020132257A1 (en) | 2001-01-31 | 2002-09-19 | Tony Giordano | Use of post-transcriptional gene silencing for identifying nucleic acid sequences that modulate the function of a cell |
WO2002066638A1 (fr) | 2001-02-22 | 2002-08-29 | Gencom Corporation | Gene recombinant contenant une sequence de repetition inversee et utilisation correspondante |
GB0104948D0 (en) | 2001-02-28 | 2001-04-18 | Novartis Res Foundation | Novel methods |
JP4210737B2 (ja) * | 2001-07-12 | 2009-01-21 | ユニバーシティー オブ マサチューセッツ | 遺伝子サイレンシングを仲介する低分子干渉リボ核酸のインビボにおける製造方法 |
US10590418B2 (en) * | 2001-07-23 | 2020-03-17 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for RNAi mediated inhibition of gene expression in mammals |
GB0118223D0 (en) | 2001-07-26 | 2001-09-19 | Univ Sheffield | Stem loop RNA |
US20030198627A1 (en) | 2001-09-01 | 2003-10-23 | Gert-Jan Arts | siRNA knockout assay method and constructs |
WO2003029459A2 (en) * | 2001-09-28 | 2003-04-10 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Micro-rna molecules |
DE10163098B4 (de) | 2001-10-12 | 2005-06-02 | Alnylam Europe Ag | Verfahren zur Hemmung der Replikation von Viren |
DE10230997A1 (de) | 2001-10-26 | 2003-07-17 | Ribopharma Ag | Medikament zur Erhöhung der Wirksamkeit eines Rezeptor-vermittelt Apoptose in Tumorzellen auslösenden Arzneimittels |
US20030148519A1 (en) * | 2001-11-14 | 2003-08-07 | Engelke David R. | Intracellular expression and delivery of siRNAs in mammalian cells |
CA2468955A1 (en) | 2001-11-28 | 2003-06-05 | Toudai Tlo, Ltd. | Sirna expression system and process for producing functional gene knockdown cell or the like using the same |
WO2003046173A1 (fr) * | 2001-11-28 | 2003-06-05 | Center For Advanced Science And Technology Incubation, Ltd. | Systeme d'expression d'arn si et procede de production de cellules d'inactivation de genes fonctionnelles et analogues au moyen de ce systeme |
DE10202419A1 (de) | 2002-01-22 | 2003-08-07 | Ribopharma Ag | Verfahren zur Hemmung der Expression eines durch eine Chromosomen-Aberration entstandenen Zielgens |
US20030166282A1 (en) | 2002-02-01 | 2003-09-04 | David Brown | High potency siRNAS for reducing the expression of target genes |
US20030180756A1 (en) * | 2002-03-21 | 2003-09-25 | Yang Shi | Compositions and methods for suppressing eukaryotic gene expression |
WO2003093441A2 (en) * | 2002-05-03 | 2003-11-13 | Duke University | A method of regulating gene expression |
AU2002951347A0 (en) | 2002-09-09 | 2002-09-26 | Benitec Australia Ltd | Genetic silencing |
JP2005026805A (ja) * | 2003-06-30 | 2005-01-27 | Renesas Technology Corp | 半導体集積回路 |
US7485468B2 (en) | 2004-10-15 | 2009-02-03 | Galapagos Bv | Molecular targets and compounds, and methods to identify the same, useful in the treatment of joint degenerative and inflammatory diseases |
-
2002
- 2002-07-12 JP JP2003512247A patent/JP4210737B2/ja not_active Expired - Lifetime
- 2002-07-12 US US10/195,034 patent/US7691995B2/en active Active
- 2002-07-12 BR BR0211111-0A patent/BR0211111A/pt not_active IP Right Cessation
- 2002-07-12 EP EP10183026A patent/EP2345720A3/en not_active Withdrawn
- 2002-07-12 IL IL15975602A patent/IL159756A0/xx active IP Right Grant
- 2002-07-12 KR KR1020097006537A patent/KR101021695B1/ko active IP Right Grant
- 2002-07-12 CA CA2921821A patent/CA2921821A1/en not_active Abandoned
- 2002-07-12 CA CA2453183A patent/CA2453183C/en not_active Expired - Lifetime
- 2002-07-12 ES ES10183024.8T patent/ES2609014T3/es not_active Expired - Lifetime
- 2002-07-12 ES ES02746979.0T patent/ES2566561T3/es not_active Expired - Lifetime
- 2002-07-12 KR KR10-2004-7000474A patent/KR20040022449A/ko active Search and Examination
- 2002-07-12 EP EP02746979.0A patent/EP1412371B1/en not_active Expired - Lifetime
- 2002-07-12 EP EP10183024.8A patent/EP2360251B1/en not_active Expired - Lifetime
- 2002-07-12 ES ES07023866.2T patent/ES2606290T3/es not_active Expired - Lifetime
- 2002-07-12 WO PCT/US2002/022010 patent/WO2003006477A1/en active Application Filing
-
2004
- 2004-01-07 IL IL159756A patent/IL159756A/en active IP Right Review Request
-
2008
- 2008-03-26 US US12/079,531 patent/US7893036B2/en not_active Expired - Lifetime
-
2010
- 2010-03-19 US US12/727,783 patent/US8530438B2/en not_active Expired - Lifetime
- 2010-03-23 US US12/729,360 patent/US8557785B2/en not_active Expired - Lifetime
- 2010-04-15 IL IL205128A patent/IL205128A/en active IP Right Grant
-
2011
- 2011-02-21 US US13/031,522 patent/US8232260B2/en not_active Expired - Lifetime
-
2013
- 2013-09-09 US US14/021,845 patent/US9175287B2/en not_active Expired - Lifetime
-
2015
- 2015-09-15 US US14/854,878 patent/US9850487B2/en not_active Expired - Lifetime
-
2017
- 2017-11-15 US US15/814,353 patent/US10731155B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2609014T3 (es) | Producción in vivo de ARN de interferencia pequeños que median el silenciamiento génico | |
Zerucha et al. | A highly conserved enhancer in the Dlx5/Dlx6Intergenic region is the site of cross-regulatory interactions betweenDlx genes in the embryonic forebrain | |
Lee et al. | Suppression of myostatin with vector-based RNA interference causes a double-muscle effect in transgenic zebrafish | |
ES2237747T3 (es) | Animales transgenicos no humanos que carecen de proteinas prionicas. | |
US7931902B2 (en) | Gene disruptions, compositions and methods relating thereto | |
Kondo et al. | Control of colinearity in AbdB genes of the mouse HoxD complex | |
KR20040072643A (ko) | siRNA 발현시스템 및 이것을 이용한 기능유전자넉다운 세포 등의 생산방법 | |
US20090313707A1 (en) | Novel Gene Disruptions, Compositions and Methods Relating Thereto | |
Pittoggi et al. | Generation of biologically active retro‐genes upon interaction of mouse spermatozoa with exogenous DNA | |
US20040231009A1 (en) | Composition and methods for the therapeutic use of an atonal-associated sequence for deafness, osteoarthritis and abnormal cell proliferation | |
Sciamanna et al. | Sperm endogenous reverse transcriptase as mediator of new genetic information | |
ZA200802556B (en) | Novel gene disruptions, compositions and methods relating thereto | |
Farber et al. | The zebrafish annexin gene family | |
JPWO2005003342A1 (ja) | メチル化を利用したトランスジェニック生物を作製する方法およびシステム | |
Graziotto et al. | Decreased levels of the RNA splicing factor Prpf3 in mice and zebrafish do not cause photoreceptor degeneration | |
US20090048111A1 (en) | Rna interference using a universal target | |
KR20050040517A (ko) | 허혈성 질환에 대한 저항성을 나타내는 형질전환 생쥐 | |
Tseng et al. | chinmo-mutant spermatogonial stem cells cause mitotic drive by evicting non-mutant neighbors from the niche | |
JPWO2005054463A1 (ja) | レトロトランスポゾンを用いた哺乳動物のゲノム改変技術の開発 | |
Ibayashi et al. | mRNA decapping factor Dcp1a is essential for embryonic growth in mice | |
Koga et al. | Overexpression of Polycomb-group gene rae28 in cardiomyocytes does not complement abnormal cardiac morphogenesis in mice lacking rae28 but causes dilated cardiomyopathy | |
J. Babu et al. | Transgenic mouse models for cardiac dysfunction by a specific gene manipulation | |
Chen et al. | Augmentation of thermotolerance in primary skin fibroblasts from a transgenic pig overexpressing the porcine HSP70. 2 | |
JP5219185B2 (ja) | 多発性嚢胞腎モデル小型魚類及びその利用 | |
JP4510490B2 (ja) | Jab1/COP9シグナロソームを利用した細胞増殖等の制御方法 |