CA2690730C - Reversible sirna-based silencing of mutant and endogenous wild-type huntingtin gene and its application for the treatment of huntington's disease - Google Patents
Reversible sirna-based silencing of mutant and endogenous wild-type huntingtin gene and its application for the treatment of huntington's disease Download PDFInfo
- Publication number
- CA2690730C CA2690730C CA2690730A CA2690730A CA2690730C CA 2690730 C CA2690730 C CA 2690730C CA 2690730 A CA2690730 A CA 2690730A CA 2690730 A CA2690730 A CA 2690730A CA 2690730 C CA2690730 C CA 2690730C
- Authority
- CA
- Canada
- Prior art keywords
- acid molecule
- short interfering
- ribonucleic acid
- double
- interfering ribonucleic
- 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 - Fee Related
Links
- 208000023105 Huntington disease Diseases 0.000 title claims abstract description 72
- 108090000623 proteins and genes Proteins 0.000 title claims abstract description 66
- 238000011282 treatment Methods 0.000 title abstract description 21
- 108020004459 Small interfering RNA Proteins 0.000 title description 49
- 230000030279 gene silencing Effects 0.000 title description 46
- 230000002441 reversible effect Effects 0.000 title description 4
- 230000014509 gene expression Effects 0.000 claims abstract description 127
- 241000282414 Homo sapiens Species 0.000 claims abstract description 89
- 230000002452 interceptive effect Effects 0.000 claims abstract description 53
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 39
- 238000011808 rodent model Methods 0.000 claims abstract description 13
- 239000013598 vector Substances 0.000 claims description 87
- 229960003722 doxycycline Drugs 0.000 claims description 77
- 229920002477 rna polymer Polymers 0.000 claims description 69
- 125000003729 nucleotide group Chemical group 0.000 claims description 65
- 239000002773 nucleotide Substances 0.000 claims description 62
- 230000000692 anti-sense effect Effects 0.000 claims description 30
- 230000000295 complement effect Effects 0.000 claims description 20
- 230000001105 regulatory effect Effects 0.000 claims description 19
- 108091034117 Oligonucleotide Proteins 0.000 claims description 18
- 239000013604 expression vector Substances 0.000 claims description 16
- 108091028043 Nucleic acid sequence Proteins 0.000 claims description 14
- 230000035897 transcription Effects 0.000 claims description 9
- 238000013518 transcription Methods 0.000 claims description 9
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 101001030705 Homo sapiens Huntingtin Proteins 0.000 claims description 5
- 102000054185 human HTT Human genes 0.000 claims description 5
- 230000000977 initiatory effect Effects 0.000 claims description 5
- 230000005026 transcription initiation Effects 0.000 claims description 5
- 230000005030 transcription termination Effects 0.000 claims description 4
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 239000002213 purine nucleotide Substances 0.000 claims description 3
- 150000003212 purines Chemical class 0.000 claims description 3
- 150000003230 pyrimidines Chemical class 0.000 claims description 3
- 230000002238 attenuated effect Effects 0.000 claims description 2
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims 1
- 102000039446 nucleic acids Human genes 0.000 abstract description 28
- 108020004707 nucleic acids Proteins 0.000 abstract description 28
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 244000097202 Rathbunia alamosensis Species 0.000 description 87
- 235000009776 Rathbunia alamosensis Nutrition 0.000 description 87
- 101150054147 sina gene Proteins 0.000 description 87
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 77
- 210000004027 cell Anatomy 0.000 description 74
- 239000004055 small Interfering RNA Substances 0.000 description 59
- 241001465754 Metazoa Species 0.000 description 49
- 241000700159 Rattus Species 0.000 description 45
- 108091027967 Small hairpin RNA Proteins 0.000 description 33
- 210000001577 neostriatum Anatomy 0.000 description 33
- 241000699670 Mus sp. Species 0.000 description 29
- 238000010186 staining Methods 0.000 description 27
- 102000012749 Dopamine and cAMP-Regulated Phosphoprotein 32 Human genes 0.000 description 26
- 108010090047 Dopamine and cAMP-Regulated Phosphoprotein 32 Proteins 0.000 description 26
- 241000699666 Mus <mouse, genus> Species 0.000 description 24
- 230000008685 targeting Effects 0.000 description 24
- 238000002347 injection Methods 0.000 description 22
- 239000007924 injection Substances 0.000 description 22
- 108020004999 messenger RNA Proteins 0.000 description 22
- 238000002474 experimental method Methods 0.000 description 20
- 108090000848 Ubiquitin Proteins 0.000 description 19
- 102000044159 Ubiquitin Human genes 0.000 description 19
- 239000005090 green fluorescent protein Substances 0.000 description 19
- 230000007774 longterm Effects 0.000 description 19
- 238000000034 method Methods 0.000 description 19
- 230000007170 pathology Effects 0.000 description 19
- 230000000694 effects Effects 0.000 description 18
- 210000002569 neuron Anatomy 0.000 description 18
- 102000004169 proteins and genes Human genes 0.000 description 18
- 108700008625 Reporter Genes Proteins 0.000 description 17
- 238000001727 in vivo Methods 0.000 description 17
- 210000004556 brain Anatomy 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 101150043003 Htt gene Proteins 0.000 description 14
- 230000003902 lesion Effects 0.000 description 14
- 239000004098 Tetracycline Substances 0.000 description 13
- 230000001404 mediated effect Effects 0.000 description 13
- 229960002180 tetracycline Drugs 0.000 description 13
- 229930101283 tetracycline Natural products 0.000 description 13
- 235000019364 tetracycline Nutrition 0.000 description 13
- 150000003522 tetracyclines Chemical class 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 12
- 102000053602 DNA Human genes 0.000 description 12
- 101001030698 Mus musculus Huntingtin Proteins 0.000 description 12
- 230000009467 reduction Effects 0.000 description 12
- 101001030728 Rattus norvegicus Huntingtin Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 230000036961 partial effect Effects 0.000 description 11
- 108700028369 Alleles Proteins 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- 108010040003 polyglutamine Proteins 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 230000002779 inactivation Effects 0.000 description 9
- 238000001543 one-way ANOVA Methods 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- 230000003828 downregulation Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000013612 plasmid Substances 0.000 description 8
- 238000011002 quantification Methods 0.000 description 8
- 108700024394 Exon Proteins 0.000 description 7
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 7
- 241000713666 Lentivirus Species 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 230000003321 amplification Effects 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 238000003199 nucleic acid amplification method Methods 0.000 description 7
- 238000003757 reverse transcription PCR Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 102100031277 Calcineurin B homologous protein 1 Human genes 0.000 description 6
- 108091081021 Sense strand Proteins 0.000 description 6
- 230000009368 gene silencing by RNA Effects 0.000 description 6
- 210000004962 mammalian cell Anatomy 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 238000001890 transfection Methods 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 5
- 206010061818 Disease progression Diseases 0.000 description 5
- -1 P.A. Substances 0.000 description 5
- 241000283984 Rodentia Species 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000005750 disease progression Effects 0.000 description 5
- 230000006870 function Effects 0.000 description 5
- 238000009396 hybridization Methods 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000013603 viral vector Substances 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 4
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 241001529936 Murinae Species 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 4
- 108091030071 RNAI Proteins 0.000 description 4
- 238000010240 RT-PCR analysis Methods 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000012226 gene silencing method Methods 0.000 description 4
- 238000012735 histological processing Methods 0.000 description 4
- 101150114736 hit gene Proteins 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000010208 microarray analysis Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 230000007171 neuropathology Effects 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 108090000765 processed proteins & peptides Proteins 0.000 description 4
- 238000004445 quantitative analysis Methods 0.000 description 4
- 238000011552 rat model Methods 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 238000010200 validation analysis Methods 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- 241000796533 Arna Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- 102000009572 RNA Polymerase II Human genes 0.000 description 3
- 108010009460 RNA Polymerase II Proteins 0.000 description 3
- 238000000540 analysis of variance Methods 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000001415 gene therapy Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000000370 laser capture micro-dissection Methods 0.000 description 3
- 238000001001 laser micro-dissection Methods 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 210000004898 n-terminal fragment Anatomy 0.000 description 3
- 230000004770 neurodegeneration Effects 0.000 description 3
- 208000015122 neurodegenerative disease Diseases 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 238000003068 pathway analysis Methods 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- 229920000155 polyglutamine Polymers 0.000 description 3
- 238000010149 post-hoc-test Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 210000003625 skull Anatomy 0.000 description 3
- 238000007619 statistical method Methods 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 238000011830 transgenic mouse model Methods 0.000 description 3
- 241000701161 unidentified adenovirus Species 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 208000035657 Abasia Diseases 0.000 description 2
- 101100042630 Caenorhabditis elegans sin-3 gene Proteins 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 101100532034 Drosophila melanogaster RTase gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 102000014450 RNA Polymerase III Human genes 0.000 description 2
- 108010078067 RNA Polymerase III Proteins 0.000 description 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 2
- 102000000574 RNA-Induced Silencing Complex Human genes 0.000 description 2
- 108010016790 RNA-Induced Silencing Complex Proteins 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- 108091028664 Ribonucleotide Proteins 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 description 2
- 238000003639 Student–Newman–Keuls (SNK) method Methods 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 239000007976 Tris-NaCl-Tween buffer Substances 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000009825 accumulation Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 238000003491 array Methods 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000010877 cognitive disease Diseases 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000005547 deoxyribonucleotide Substances 0.000 description 2
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 230000003467 diminishing effect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 108010048367 enhanced green fluorescent protein Proteins 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 210000001222 gaba-ergic neuron Anatomy 0.000 description 2
- 230000003371 gabaergic effect Effects 0.000 description 2
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 2
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 230000003990 molecular pathway Effects 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 230000032361 posttranscriptional gene silencing Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000002336 ribonucleotide Substances 0.000 description 2
- 125000002652 ribonucleotide group Chemical group 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 201000003624 spinocerebellar ataxia type 1 Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 xylazine Drugs 0.000 description 2
- 101150084750 1 gene Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-BIIVOSGPSA-N 2'-deoxythymidine Natural products O=C1NC(=O)C(C)=CN1[C@@H]1O[C@@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-BIIVOSGPSA-N 0.000 description 1
- HSTOKWSFWGCZMH-UHFFFAOYSA-N 3,3'-diaminobenzidine Chemical compound C1=C(N)C(N)=CC=C1C1=CC=C(N)C(N)=C1 HSTOKWSFWGCZMH-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- OPIFSICVWOWJMJ-AEOCFKNESA-N 5-bromo-4-chloro-3-indolyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CNC2=CC=C(Br)C(Cl)=C12 OPIFSICVWOWJMJ-AEOCFKNESA-N 0.000 description 1
- IWFHOSULCAJGRM-UAKXSSHOSA-N 5-bromouridine 5'-triphosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@@H](O)[C@@H]1N1C(=O)NC(=O)C(Br)=C1 IWFHOSULCAJGRM-UAKXSSHOSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- 241000945470 Arcturus Species 0.000 description 1
- 102000007372 Ataxin-1 Human genes 0.000 description 1
- 108010032963 Ataxin-1 Proteins 0.000 description 1
- 102000014461 Ataxins Human genes 0.000 description 1
- 108010078286 Ataxins Proteins 0.000 description 1
- 241000726103 Atta Species 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008748 Chorea Diseases 0.000 description 1
- 206010008752 Choreiform movements Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 108010068682 Cyclophilins Proteins 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 101710177611 DNA polymerase II large subunit Proteins 0.000 description 1
- 101710184669 DNA polymerase II small subunit Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 241001123946 Gaga Species 0.000 description 1
- 102000002464 Galactosidases Human genes 0.000 description 1
- 108010093031 Galactosidases Proteins 0.000 description 1
- 108050004784 Huntingtin Proteins 0.000 description 1
- 102000016252 Huntingtin Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 208000002569 Machado-Joseph Disease Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 108091027974 Mature messenger RNA Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 101710160107 Outer membrane protein A Proteins 0.000 description 1
- 238000012408 PCR amplification Methods 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000011755 Phosphoglycerate Kinase Human genes 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004721 Polyphenylene oxide Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000004792 Prolene Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 101100338540 Rattus norvegicus Htt gene Proteins 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000003661 Ribonuclease III Human genes 0.000 description 1
- 108010057163 Ribonuclease III Proteins 0.000 description 1
- CGNLCCVKSWNSDG-UHFFFAOYSA-N SYBR Green I Chemical compound CN(C)CCCN(CCC)C1=CC(C=C2N(C3=CC=CC=C3S2)C)=C2C=CC=CC2=[N+]1C1=CC=CC=C1 CGNLCCVKSWNSDG-UHFFFAOYSA-N 0.000 description 1
- 208000036834 Spinocerebellar ataxia type 3 Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 101001099217 Thermotoga maritima (strain ATCC 43589 / DSM 3109 / JCM 10099 / NBRC 100826 / MSB8) Triosephosphate isomerase Proteins 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 108091034131 VA RNA Proteins 0.000 description 1
- 108091093126 WHP Posttrascriptional Response Element Proteins 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- GKVHYBAWZAYQDO-XVFCMESISA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-(2-oxo-4-sulfanylidenepyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O1[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@@H](O)[C@@H]1N1C(=O)NC(=S)C=C1 GKVHYBAWZAYQDO-XVFCMESISA-N 0.000 description 1
- YRUWXBKVSXSSGS-AESZWTTRSA-N [[(2r,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphinothioyl] phosphono hydrogen phosphate Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](COP(O)(=S)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O YRUWXBKVSXSSGS-AESZWTTRSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 230000003376 axonal effect Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000008236 biological pathway Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000011496 cAMP-mediated signaling Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000004700 cellular uptake Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000004186 co-expression Effects 0.000 description 1
- 238000012761 co-transfection Methods 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 210000003618 cortical neuron Anatomy 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- MWEQTWJABOLLOS-UHFFFAOYSA-L disodium;[[[5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-oxidophosphoryl] hydrogen phosphate;trihydrate Chemical compound O.O.O.[Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP([O-])(=O)OP(O)([O-])=O)C(O)C1O MWEQTWJABOLLOS-UHFFFAOYSA-L 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000005584 early death Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000003090 exacerbative effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 210000001822 immobilized cell Anatomy 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000010468 interferon response Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000007914 intraventricular administration Methods 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 230000020796 long term synaptic depression Effects 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000011880 melting curve analysis Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000004897 n-terminal region Anatomy 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 230000007121 neuropathological change Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- MCYTYTUNNNZWOK-LCLOTLQISA-N penetratin Chemical compound C([C@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CCCNC(N)=N)[C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(N)=O)C1=CC=CC=C1 MCYTYTUNNNZWOK-LCLOTLQISA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000570 polyether Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000004063 proteosomal degradation Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 230000011218 segmentation Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 230000001743 silencing effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000010473 stable expression Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 101150061166 tetR gene Proteins 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000012301 transgenic model Methods 0.000 description 1
- 238000011824 transgenic rat model Methods 0.000 description 1
- 230000010474 transient expression Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000005199 ultracentrifugation Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000008096 xylene Substances 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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 nucleic acids [NA]
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Biomedical Technology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- General Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Plant Pathology (AREA)
- Biophysics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Neurology (AREA)
- Psychology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07290751.2 | 2007-06-18 | ||
| EP07290751A EP2014769B1 (en) | 2007-06-18 | 2007-06-18 | Reversible siRNAa-based silencing of mutated and endogenous wild-type huntingtin gene and its application for the treatment of Huntington's disease |
| PCT/IB2008/002603 WO2009007855A2 (en) | 2007-06-18 | 2008-06-18 | Reversible sirna-based silencing of mutant and endogenous wild-type huntingtin gene and its application for the treatment of huntington's disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2690730A1 CA2690730A1 (en) | 2009-01-15 |
| CA2690730C true CA2690730C (en) | 2018-07-31 |
Family
ID=38476952
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2690730A Expired - Fee Related CA2690730C (en) | 2007-06-18 | 2008-06-18 | Reversible sirna-based silencing of mutant and endogenous wild-type huntingtin gene and its application for the treatment of huntington's disease |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US8217018B2 (enExample) |
| EP (1) | EP2014769B1 (enExample) |
| JP (1) | JP5401451B2 (enExample) |
| AT (1) | ATE462787T1 (enExample) |
| CA (1) | CA2690730C (enExample) |
| DE (1) | DE602007005629D1 (enExample) |
| WO (1) | WO2009007855A2 (enExample) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009135322A1 (en) * | 2008-05-09 | 2009-11-12 | The Universtity Of British Columbia | Methods and compositions for the treatment of huntington's disease |
| US8679750B2 (en) | 2008-05-09 | 2014-03-25 | The University Of British Columbia | Methods and compositions for the treatment of Huntington'S disease |
| WO2010064146A2 (en) | 2008-12-02 | 2010-06-10 | Chiralgen, Ltd. | Method for the synthesis of phosphorus atom modified nucleic acids |
| CA2767253A1 (en) | 2009-07-06 | 2011-01-13 | Ontorii, Inc. | Novel nucleic acid prodrugs and methods of use thereof |
| AU2011213562B2 (en) | 2010-02-08 | 2016-07-07 | Ionis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| EP2534262B1 (en) | 2010-02-08 | 2016-12-14 | Ionis Pharmaceuticals, Inc. | Selective reduction of allelic variants |
| EP2591356A1 (en) * | 2010-07-09 | 2013-05-15 | Ecole Polytechnique Fédérale de Lausanne (EPFL) | Method for in-vitro monitoring of neuronal disorders and use thereof |
| WO2012039448A1 (ja) | 2010-09-24 | 2012-03-29 | 株式会社キラルジェン | 不斉補助基 |
| CN103796657B (zh) | 2011-07-19 | 2017-07-11 | 波涛生命科学有限公司 | 合成官能化核酸的方法 |
| WO2013022966A1 (en) | 2011-08-11 | 2013-02-14 | Isis Pharmaceuticals, Inc. | Linkage modified gapped oligomeric compounds and uses thereof |
| AU2013225950B2 (en) | 2012-02-29 | 2018-02-15 | Sangamo Therapeutics, Inc. | Methods and compositions for treating huntington's disease |
| WO2014010250A1 (en) | 2012-07-13 | 2014-01-16 | Chiralgen, Ltd. | Asymmetric auxiliary group |
| CA2879066C (en) | 2012-07-13 | 2019-08-13 | Shin Nippon Biomedical Laboratories, Ltd. | Chiral nucleic acid adjuvant |
| JP6453212B2 (ja) | 2012-07-13 | 2019-01-16 | ウェイブ ライフ サイエンシズ リミテッドＷａｖｅ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ Ｌｔｄ． | キラル制御 |
| HK1212597A1 (zh) * | 2012-10-15 | 2016-06-17 | Isis Pharmaceuticals, Inc. | 用於調節c90rf72表達的組合物 |
| WO2014062736A1 (en) | 2012-10-15 | 2014-04-24 | Isis Pharmaceuticals, Inc. | Methods for monitoring c9orf72 expression |
| CN105143203A (zh) | 2013-04-17 | 2015-12-09 | 辉瑞大药厂 | 用于治疗心血管疾病的n-哌啶-3-基苯甲酰胺衍生物 |
| SG11201602597YA (en) | 2013-10-11 | 2016-05-30 | Ionis Pharmaceuticals Inc | Compositions for modulating c9orf72 expression |
| MX391904B (es) * | 2013-11-11 | 2025-03-12 | Sangamo Biosciences Inc | Un represor genetico para usarse en el tratamiento de la enfermedad de huntington. |
| JPWO2015108046A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗アレルギー作用を有するキラル核酸アジュバンド及び抗アレルギー剤 |
| JPWO2015108048A1 (ja) | 2014-01-15 | 2017-03-23 | 株式会社新日本科学 | 抗腫瘍作用を有するキラル核酸アジュバンド及び抗腫瘍剤 |
| WO2015108047A1 (ja) | 2014-01-15 | 2015-07-23 | 株式会社新日本科学 | 免疫誘導活性を有するキラル核酸アジュバンド及び免疫誘導活性剤 |
| KR20230152178A (ko) | 2014-01-16 | 2023-11-02 | 웨이브 라이프 사이언시스 리미티드 | 키랄 디자인 |
| CN106413760B (zh) * | 2014-05-08 | 2020-01-14 | 桑格摩生物科学股份有限公司 | 用于治疗亨廷顿病的方法和组合物 |
| SG11201708468YA (en) | 2015-04-16 | 2017-11-29 | Ionis Pharmaceuticals Inc | Compositions for modulating c9orf72 expression |
| MA43072A (fr) | 2015-07-22 | 2018-05-30 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
| WO2017079291A1 (en) | 2015-11-02 | 2017-05-11 | Ionis Pharmaceuticals, Inc. | Compounds and methods for modulating c90rf72 |
| MA45270A (fr) | 2016-05-04 | 2017-11-09 | Wave Life Sciences Ltd | Compositions d'oligonucléotides et procédés associés |
-
2007
- 2007-06-18 DE DE602007005629T patent/DE602007005629D1/de active Active
- 2007-06-18 EP EP07290751A patent/EP2014769B1/en not_active Not-in-force
- 2007-06-18 AT AT07290751T patent/ATE462787T1/de not_active IP Right Cessation
-
2008
- 2008-06-18 US US12/665,137 patent/US8217018B2/en not_active Expired - Fee Related
- 2008-06-18 CA CA2690730A patent/CA2690730C/en not_active Expired - Fee Related
- 2008-06-18 JP JP2010512808A patent/JP5401451B2/ja not_active Expired - Fee Related
- 2008-06-18 WO PCT/IB2008/002603 patent/WO2009007855A2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| US20100299768A1 (en) | 2010-11-25 |
| WO2009007855A3 (en) | 2009-04-02 |
| JP2010530239A (ja) | 2010-09-09 |
| EP2014769B1 (en) | 2010-03-31 |
| DE602007005629D1 (de) | 2010-05-12 |
| CA2690730A1 (en) | 2009-01-15 |
| EP2014769A1 (en) | 2009-01-14 |
| US8217018B2 (en) | 2012-07-10 |
| WO2009007855A2 (en) | 2009-01-15 |
| ATE462787T1 (de) | 2010-04-15 |
| JP5401451B2 (ja) | 2014-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2690730C (en) | Reversible sirna-based silencing of mutant and endogenous wild-type huntingtin gene and its application for the treatment of huntington's disease | |
| AU2015264263B2 (en) | Huntington's disease therapeutic compounds | |
| US8779116B2 (en) | SiRNA-mediated gene silencing | |
| US8524879B2 (en) | RNA interference suppresion of neurodegenerative diseases and methods of use thereof | |
| JP3642573B2 (ja) | ｓｉＲＮＡ発現システムおよびこれを用いた機能遺伝子ノックダウン細胞等の生産方法 | |
| US20040002077A1 (en) | siRNA expression system and method for producing functional gene knock-down cell using the system | |
| ZA200501020B (en) | Allele-specific siRNA-mediated gene silencing | |
| US20100086526A1 (en) | Nucleic acid constructs and methods for specific silencing of h19 | |
| IL194114A (en) | Use of RNA compound interferes with the preparation of drugs for the treatment of central nervous system disorder, medicinal preparations for intraperitoneal administration containing one or more SINAs directed to the gene expressed in the central nervous system. | |
| JP2010512794A (ja) | 核酸の発現のための組成物及び方法 | |
| Cazzin | Development of viral vector-mediated RNA interference targeting several P2X receptors in the rat central nervous system | |
| HK1236224B (en) | Huntington's disease therapeutic compounds | |
| HK1236224A1 (en) | Huntington's disease therapeutic compounds | |
| EP1581635A2 (en) | Sirna-mediated gene silencing |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request |
Effective date: 20130529 |
|
| MKLA | Lapsed |
Effective date: 20220301 |
|
| MKLA | Lapsed |
Effective date: 20200831 |