JP6841507B2 - アンジェルマン症候群の遺伝子治療法のための組み換えube3a遺伝子 - Google Patents
アンジェルマン症候群の遺伝子治療法のための組み換えube3a遺伝子 Download PDFInfo
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Classifications
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- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/52—Genes encoding for enzymes or proenzymes
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/104—Aminoacyltransferases (2.3.2)
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- C12N2750/00011—Details
- C12N2750/14011—Parvoviridae
- C12N2750/14111—Dependovirus, e.g. adenoassociated viruses
- C12N2750/14141—Use of virus, viral particle or viral elements as a vector
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Description
atgaagcgag cagctgcaaa gcatctaata gaacgctact accatcagtt aactgagggc tgtggaaatg aggcctgcac gaatgagttt tgtgcttcct gtccaacttt tcttcgtatg gataacaatg cagcagctat taaagccctt gagctttata aaattaatgc aaaactctgt gatcctcatc cctccaagaa aggagcaagc tcagcttacc ttgagaactc aaaaggtgca tctaacaact cagagataaa aatgaacaag aaggaaggaa aagattttaa agatgtgatt tacctaactg aagagaaagt atatgaaatt tatgaatttt gtagagagag tgaggattat tcccctttaa ttcgtgtaat tggaagaata ttttctagtg ctgaggcact ggttctgagc tttcggaaag tcaaacagca cacaaaggag gaattgaaat ctcttcaaga aaaggatgaa gacaaggatg aagatgaaaa ggaaaaagct gcatgttctg ctgctgctat ggaagaagac tcagaagcat cttcttcaag gatgggtgat agttcacagg gagacaacaa tgtacaaaaa ttaggtcctg atgatgtgac tgtggatatt gatgctatta gaagggtcta cagcagtttg ctcgctaatg aaaaattaga aactgccttc ctgaatgcac ttgtatatct gtcacctaac gtggaatgtg atttgacata tcataatgtg tatactcgag atcctaatta tctcaatttg ttcattattg taatggagaa tagtaatctc cacagtcctg aatatctgga aatggcgttg ccattatttt gcaaagctat gtgtaagcta ccccttgaag ctcaaggaaa actgattagg ctgtggtcta aatacagtgc tgaccagatt cggagaatga tggaaacatt tcagcaactt attacctaca aagtcataag caatgaattt aatagccgaa atctagtgaa tgatgatgat gccattgttg ctgcttcaaa gtgtttgaaa atggtttact atgcaaatgt agtgggaggg gatgtggaca caaatcataa tgaggaagat gatgaagaac ccatacctga gtccagcgaa ttaacacttc aggagcttct gggagatgaa agaagaaata agaaaggtcc tcgagtggat ccactagaaa ccgaacttgg cgttaaaact ctagactgtc gaaaaccact tatctccttt gaagaattca ttaatgaacc actgaatgat gttctagaaa tggacaaaga ttataccttt ttcaaagttg aaacagagaa caaattctct tttatgacat gtccctttat attgaatgct gtcacaaaga atctgggatt atattatgac aatagaattc gcatgtacag tgaaagaaga atcactgttc tttacagcct agttcaagga cagcagttga atccgtattt gagactcaaa gtcagacgtg accatattat agatgatgca ctggtccggc tagagatgat tgctatggaa aatcctgcag acttgaagaa gcagttgtat gtggaatttg aaggagaaca aggagtaatg agggaggcgt ttccaaagag ttttttcagt tgggttgtgg aggaaatttt taatccaaat attggtatgt tcacatatga tgaagctacg aaattatttt ggtttaatcc atcttctttt gaaactgagg gtcaggttta ctctgattgg catatcctgg gtctggctat ttacaataat tgtatactgg atgtccattt tcccatggtt gtatacagga agctaatggg gaaaaaagga acctttcgtg acttgggaga ctctcaccca gttttatatc agagtttaaa ggatttattg gaatatgaag ggagtgtgga agatgatatg atgatcactt tccagatatc acagacagat ctttttggta acccaatgat gtatgatcta aaagaaaatg gtgataaaat tccaattaca aatgaaaaca ggaaggaatt tgtcaatctc tattcagact acattctcaa taaatctgta gaaaaacaat tcaaggcatt tcgcagaggt tttcatatgg tgactaatga atcgccctta aaatacttat tcagaccaga agaaattgaa ttgcttatat gtggaagccg gaatctagat ttccaggcac tagaagaaac tacagagtat gacggtggct atacgaggga atctgttgtg attagggagt tctgggaaat tgttcattcg tttacagatg aacagaaaag actctttctg cagtttacaa caggcacaga cagagcacct gttggaggac taggaaaatt gaagatgatt atagccaaaa atggcccaga cacagaaagg ttacctacat ctcatacttg ctttaatgtc cttttacttc cggaatattc aagcaaagaa aaacttaaag agagattgtt gaaggccatc acatatgcca aaggatttgg catgctgtaa (配列番号1)
から作成した。
atg gcc ctg ttg gtg cac ttc cta ccc ctg ctg gcc ctg ctt gcc ctc tgg gag ccc aaa ccc acc cag gct ttt gtc (SEQ ID No. 2)
を有し、タンパク質配列;
MALLVHFLPLLALLALWEPKPTQAFV(配列番号3)
をコードし、一方、HIV TAT配列は;
tac ggc aga aag aag agg agg cag aga agg aga (配列番号4)
であり、タンパク質配列;
YGRKKRRQRRR (配列番号5)
をコードする。
ggagtagttt actgagccac taatctaaag tttaatactg tgagtgaata ccagtgagta cctttgttaa tgtggataac caatacttgg ctataggaag ttttttagtt gtgtgtttta tnacacgtat ttgactttgt gaataattat ggcttataat ggcttgtctg ttggtatcta tgtatagcgt ttacagtttc ctttaaaaaa catgcattga gttttttaat agtccaaccc ttaaaataaa tgtgttgtat ggccacctga tctgaccact ttctttcatg ttgacatctt taattttaaa actgttttat ttagtgctta aatcttgttn acaaaattgt cttcctaagt aatatgtcta cctttttttt tggaatatgg aatattttgc taactgtttc tcaattgcat tttacagatc aggagaacct cagtctgacg acattgaagc tagccgaatg taagtgtaac ttggttgaga ctgtggttct tattttgagt tgccctagac tgctttaaat tacgtcacat tatttggaaa taatttctgg ttaaaagaaa ggaatcattt agcagtaaat gggagatagg aacataccta ctttttttcc tatcagataa ctctaaacct cggtaacagt ttactaggtt tctactacta gatagataaa tgcacacgcc taaattctta gtctttttgc ttccctggta gcagttgtag ggaaataggg aggttgagga aagagtttaa cagtctcaac gcctaccata tttaaggcat caagtactat gttatagata cagagatgcg taataattag ttttcaccct acagaaattt atattatact caagagtgaa agatgcagaa gcaaataatt tcagtcactg aggtagaatg gtatccaaaa tacaatagta acatgaagga gtactggagt accaggtatg caataggaat ctagtgtaga tggcagggaa gtaagagtgg ccaggaaatg ctaagttcag tcttgaaatg tgactgggaa tcaggcagct atcaactata agtcaaatgt ttacaagctg ttaaaaatga aatactgatt atgtaaaaga aaaccggatt gatgctttaa atagactcat tttcntaatg ctaattttta aaatgataga atcctacaan tcttagctgt aaaccttgtg atttttcagc tgttgtacta aacaacttaa gcacatatac catcagacaa gcccccntcc ccccttttaa accaaaggaa tgtatactct gttaatacag tcagtaagca ttgacattct ttatcataat atcctagaaa atatttatta actatttcac tagtcaggag ttgtggtaaa tagtgcatct ccattttcta cttctcatct tcatacacag gttaatcact tcagtgcttg actaactttt gccttgatga tatgttgagc tttgtacttg agagctgtac taatcactgt gcttattgtt tgaatgtttg gtacaggaag cgagcagctg caaagcatct aatagaacgc tactaccacc agttaactga gggctgtgga aatgaagcct gcacgaatga gttttgtgct tcctgtccaa cttttcttcg tatggataat aatgcagcag ctattaaagc cctcgagctt tataagatta atgcaaaact ctgtgatcct catccctcca agaaaggagc aagctcagct taccttgaga actcgaaagg tgcccccaac aactcctgct ctgagataaa aatgaacaag aaaggcgcta gaattgattt taaaggtaag atgttttatt ttcaattgag aattgttgcc tgaaaaccat gtgggagatt taaatgtatt agtttttatt tgttttttct tctgtgacat aaagacattt tgatatcgta gaaccaattt tttattgtgg taacggacag gaataataac tacattttac aggtctaatc attgctaatt agaagcagat catatgccaa aagttcattt gttaatagat tgatttgaac tttttaaaat tcttaggaaa aatgtattaa gtggtagtga atctccaaaa ctatttaaga gctgtattat gattaatcag tacatgacat attggttcat atttataatt aaagctatac attaatagat atcttgatta taaagaaagt ttaaactcat gatcttatta agagttatac attgttgaaa gaatgtaaaa gcatgggtga ggtcattggt ataggtaggt agttcattga aaaaaatagg taagcattaa attttgtttg ctgaatctaa gtattagata ctttaagagt tgtatatcat aaatgatatt gagcctagaa tgtttggctg ttttactttt agaacttttt gcaacagagt aaacatacat attatgaaaa taaatgttct cttttttcct ctgattttct agatgtgact tacttaacag aagagaaggt atatgaaatt cttgaattat gtagagaaag agaggattat tcccctttaa tccgtgttat tggaagagtt ttttctagtg ctgaggcatt ggtacagagc ttccggaaag ttaaacaaca caccaaggaa gaactgaaat ctcttcaagc aaaagatgaa gacaaagatg aagatgaaaa ggaaaaagct gcatgttctg ctgctgctat ggaagaagac tcagaagcat cttcctcaag gataggtgat agctcacagg gagacaacaa tttgcaaaaa ttaggccctg atgatgtgtc tgtggatatt gatgccatta gaagggtcta caccagattg ctctctaatg aaaaaattga aactgccttt ctcaatgcac ttgtatattt gtcacctaac gtggaatgtg acttgacgta tcacaatgta tactctcgag atcctaatta tctgaatttg ttcattatcg taatggagaa tagaaatctc cacagtcctg aatatctgga aatggctttg ccattatttt gcaaagcgat gagcaagcta ccccttgcag cccaaggaaa actgatcaga ctgtggtcta aatacaatgc agaccagatt cggagaatga tggagacatt tcagcaactt attacttata aagtcataag caatgaattt aacagtcgaa atctagtgaa tgatgatgat gccattgttg ctgcttcgaa gtgcttgaaa atggtttact atgcaaatgt agtgggaggg gaagtggaca caaatcacaa tgaagaagat gatgaagagc ccatccctga gtccagcgag ctgacacttc aggaactttt gggagaagaa agaagaaaca agaaaggtcc tcgagtggac cccctggaaa ctgaacttgg tgttaaaacc ctggattgtc gaaaaccact tatccctttt gaagagttta ttaatgaacc actgaatgag gttctagaaa tggataaaga ttatactttt ttcaaagtag aaacagagaa caaattctct tttatgacat gtccctttat attgaatgct gtcacaaaga atttgggatt atattatgac aatagaattc gcatgtacag tgaacgaaga atcactgttc tctacagctt agttcaagga cagcagttga atccatattt gagactcaaa gttagacgtg accatatcat agatgatgca cttgtccggg taagttgggc tgctagatta aaaacctaat aatggggata tcatgataca gttcagtgaa ttcattttaa aagtgactga aaaaaatgat accatatagc ataggaacac atggacattt ctgatcttat ataagtatta tacttttgtt gttcctgtgc aagtttatag atgtgttcta caaagtatcg gttgtattat ataatggtca tgctatcttt gaaaaagaat gggttttcta aatcttgaaa actaaatcca aagtttcttt cattcagaag agaatagagt gttggacaaa gaccagaaca agagaaatgt ggagataccc aataataagt gtggatgtgc agtcttgaac tgggagtaat ggtacagtaa aaccatacca taaaattata ggtagtgtcc aaaaaattcc atcgtgtaaa attcagagtt gcattattgt ggacttgaag aagcagttgt atgtgggacg gtatcgataa gcttgatatc gaattcctgc agcccggggg atccactagt gtggtaatta atactaagtc ttactgtgag agaccataaa ctgctttagt attcagtgta tttttcttaa ttgaaatatt taacttatga cttagtagat actaagactt aacccttgag tttctattct aataaaggac tactaatgaa caattttgag gttagacctc tactccattg tttttgctga aatgatttag ctgcttttcc atgtcctgtg tagtccagac ttaacacaca agtaataaaa tcttaattaa ttgtatgtta atttcataac aaatcagtaa agttagcttt ttactatgct agtgtctgtt ttgtgtctgt ctttttgatt atctttaaga ctgaatcttt gtcttcactg gctttttatc agtttgcttt ctgtttccat ttacatacaa aaagtcaaaa atttgtattt gtttcctaat cctactcctt gtttttattt tgtttttttc ctgatactag caatcatctt cttttcatgt ttatcttttc aatcactagc tagagatgat cgctatggaa aatcctgcag acttgaagaa gcagttgtat gtggaatttg aaggagaaca aggagttgat gagggaggtg tttccaaaga attttttcag ctggttgtgg aggaaatctt caatccagat attggtaaat acattagtaa tgtgattatg gtgtcgtatc atcttttgag ttagttattt gtttatctta ctttgtaaat attttcagct atgaagagca gcaaaagaag gatttggtat ggattaccca gaatcacaca tcatgactga atttgtaggt tttaggaact gatttgtatc actaatttat tcaaattctt ttatttctta gaaggaatat tctaatgaag gaaattatct ctttggtaaa ctgaattgaa agcactttag aatggtatat tggaacagtt ggagggattt ctttgctttt tgttgtctaa aaccatcatc aaactcacgg ttttcctgac ctgtgaactt caaagaacaa tggtttgaag agtattgaga gactgtctca caagtatgtc atgctcaaag ttcagaaaca ctagctgata tcacattaat taggtttatt tgctataaga tttcttgggg cttaatatan gtagtgttcc cccaaacttt ttgaactcca gaactctttt ctgccctaac agtagctact caggagctga ggcaggagaa ttgtttgaac ctaggaggca gaggttgcag tgagctgaga tcgtgccact ccagcccacc cctgggtaac agagcgagac tccatctcaa agaaaaaaat gaaaaattgt tttcaaaaat agtacgtgtg gtacagatat aagtaattat atttttataa atgaaacact ttggaaatgt agccattttt tgttttttta tgtttatttt tcagctatgg gtggataaag catgaatata acttttctta tgtgttagta gaaaattaga aagcttgaat ttaattaacg tatttttcta cccgatgcca ccaaattact tactacttta ttcctttggc ttcataaaat tacatatcac cattcacccc aatttatagc agatatatgt ggacattgtt ttctcaagtg ctaatataat agaaatcaat gttgcatgcc taattacata tattttaaat gttttatatg cataattatt ttaagtttat atttgtatta ttcatcagtc cttaataaaa tacaaaagta atgtattttt aaaaatcatt tcttataggt atgttcacat acgatgaatc tacaaaattg ttttggttta atccatcttc ttttgaaact gagggtcagt ttactctgat tggcatagta ctgggtctgg ctatttacaa taactgtata ctggatgtac attttcccat ggttgtctac aggaagctaa tggggaaaaa aggaactttt cgtgacttgg gagactctca cccagtaagt tctttgtcat ttttttaatt cagtctctta gattttattt aaatgcaaaa atttaattta tgtcaaaatt ttaaagtttt tgtttagaat ctttgttgat actcttatca ataagataaa aatgttttaa tctgaccgaa gtaccagaaa cacttaaaaa ctcaaagggg gacattttta tatattgctg tcagcacgaa gctttcgtaa gattgatttc atagagaagt gtttctaaac attttgtttg tgttttagtg aaatcttaag agataggtaa aaatcagagt agccctggct aagggtcttg gtagttacaa cgagtgtgcc tgctcctacc acccccaccc ccaccttgag acaccacaga atttctcata gagcacagtg tgaattctat tgctaaattg gtggtatggg gtttctcagc agagaatggg acatcacagt gactgacaat ctttctttta taggttggaa actatttggg ggactggagg gatactgtct acacttttta caatttttat tgataagatt tttgttgtct tctaagaaga gtgatataaa ttatttgttg tattttgtag ttctatggtg gcctcaattt accatttctg gttgctaggt tctatatcag agtttaaaag atttattgga gtatgaaggg aatgtggaag atgacatgat gatcactttc cagatatcac agacagatct ttttggtaac ccaatgatgt atgatctaaa ggaaaatggt gataaaattc caattacaaa tgaaaacagg aaggtaataa atgtttttat gtcacatttt gtctcttcat taacactttc aaagcatgta tgcttataat ttttaaagaa gtatctaata tagtctgtac aaaaaaaaaa caagtaacta agtttatgta aatgctagag tccacttttc taaatcttgg atataagttg gtatgaaagc acacagttgg gcactaaagc cccttttaga gaaagaggac atgaagcagg agatagttaa tagctaagtg tggttgtagt ataaagcaag aagcagggtg tttcttgtat taagctgtaa gcaggaacct catgattaag gtctttatca cagaacaaat aaaaattaca tttaatttac acatgtatat cctgtttgtg ataaaaatac atttctgaaa agtatacttt acgtcagatt tgggttctat tgactaaaat gtgttcatcg ggaatgggaa taacccagaa cataacaagc aaaaaattat gacaaatata tagtatacct ttaagaaaca tgtttatatt gatataattt tttgattaaa tattatacac actaagggta caangcacat tttcctttta tganttngat acagtagttt atgtgtcagt cagatacttc cacatttttg ctgaactgga tacagtaagc agcttaccaa atattctatg gtagaaaact nggacttcct ggtttgctta aatcaaatat attgtactct cttaaaacgg ttggcattta taaatagatg gatacatggt ttaaatgtgt ctgttnacat acctagttga gagaacctaa agaattttct gcgtctccag catttatatt cagttctgtt taatacatta tcgaaattga catttataag tatgacagtt ttgtgtatat ggccttttca tagcttaata ttggctgtaa cagagaattg tgaaattgta agaagtagtt ttctttgtag gtgtaaaatt gaatttttaa gaatattctt gacagtttta tgtatatggc cttttcatag cttaatattg gctataacag agaattgtga aattgttaag aagtaggtgt aaaattgaat ttttaagaat attcttgaat gtttttttct tggaaaaatt aaaaagctat gcagcccaat aacttgtgtt ttgtttgcat agcatattat aagaagttct tgtgattaat gttttctaca ggaatttgtc aatctttatt ctgactacat tctcaataaa tcagtagaaa aacagttcaa ggcttttcgg agaggttttc atatggtgac caatgaatct cccttaaagt acttattcag accagaagaa attgaattgc ttatatgtgg aagccgggta agaaagcagg tgtctgcaaa aagtcatgta tcgatttatt gtttgtaatg atacagtagt atagcagata actaagacat attttcttga atttgcagaa tctagatttc caagcactag aagaaactac agaatatgac ggtggctata ccagggactc tgttctgatt aggtgaggta cttagttctt cagaggaaga tttgattcac caaaggggtg tgtgattttg cttcagacct ttatctctag gtactaattc ccaaataagc aaactcacaa attgtcatct atatacttag atttgtattt gtaatataat caccattttt cagagctaat cttgtgattt atttcatgaa tgaagtgttg ttatatataa gtctcatgta atctcctgca tttggcgtat ggattatcta gtattcctca ctggttagag tatgcttact gctggttaga agataattaa aataaggcta ccatgtctgc aatttttcct ttcttttgaa ctctgcattt gtgaactgtt acatggcttc ccaggatcaa gcactttttg agtgaaatgg tagtctttta tttaattctt aagataatat gtccagatac atactagtat ttccatttta caccctaaaa aactaagccc tgaattctca cagaaagatg tagaggttcc cagttctatc tgcttttaaa caaatgccct tactactcta ctgtctactt ctgtgtacta catcatcgta tgtagttgtt tgcatttggg ccagttggtt ggggcagggg tctttttttc ttttgtccct taatctgtat cactttttcc tcccaaagtt gagttaaagg atgagtagac caggagaata aaggagaaag gataaataaa
atatataccc aaaggcacct ggagttaatt tttccaaata ttcatttcag tctttttcaa ttcataggat tttgtctttt gctcattact gactgcataa tgtgattata ccatagttta aatagtcact tcctgttact acacacttgg gttttctcaa ttttttacta ttgtagtact aatattttac tatattgtaa tctaatccaa atttttacgt attcagagct gttcaggata aatttgcttg gaaattttta aatcaccaga agtgatacta tcctgataat taacttccaa gttgtctctt aatatagttt taatgcaaat cataagctta tgttagtacc agtcataatg aatgccaaac tgaaaccagt attgtatttt ttctcattag ggagttctgg gaaatcgttc attcatttac agatgaacag aaaagactct tcttgcagtt tacaacgggc acagacagag cacctgtggg aggactagga aaattaaaga tgattatagc caaaaatggc ccagacacag aaaggtaggt aattattaac ttgtgactgt atacctaccg aaaaccttgc attcctcgtc acatacatat gaactgtctt tatagtttct gagcacattc gtgattttat atacaaatcc ccaaatcata ttagacaatt gagaaaatac tttgctgtca ttgtgtgagg aaacttttaa gaaattgccc tagttaaaaa ttattatggg gctcacattg gtttggaatc aaattagtgt gattcattta cttttttgat tcccagcttg ttaattgaaa gccatataac atgatcatct atttagaatg gttacattga ggctcggaag attatcattt gattgtgcta gaatcctgtt atcaaatcat tttcttagtc atattgccag cagtgtttct aataagcatt taagagcaca cactttgcag tcttgtaaaa caggtttgag tattttctcc accttagagg aagttacttg acttctcagt gacctaacct ctaaagtgca tttactgatg tcctctctgt ggttttgttg tggaaagatt tagttaaatg aactgtaaga attcagtacc taaaatggta tctgttatgt agtaaaaact caatggatac agtatcttat catcgtcact agctttgagt aatttatagg ataaaggcaa cttggtagtt acacaacaaa aagtttatga tttgcattaa tgtatagttt gcattgcaga ccgtctcaac tatatacaat ctaaaaatag gagcatttaa ttctaagtgt atttcccatg acttacagtt ttcctgtttt tttccccttt tctctattta ggttacctac atctcatact tgctttaatg tgcttttact tccggaatac tcaagcaaag aaaaacttaa agagagattg ttgaaggcca tcacgtatgc caaaggattt ggcatgctgt aaaacaaaac aaaacaaaat aaaacaaaaa aaaggaagga aaaaaaaaga aaaaatttaa aaaattttaa aaatataacg agggataaat ttt(配列番号6)から作成し、このcDNAは;
MKRAAAKHLIERYYHQLTEGCGNEACTNEFCASCPTFLRMDNNAAAIKALELYKINAKLCDPHPSKKGASSAYLENSKGAPNNSCSEIKMNKKGARIDFKDVTYLTEEKVYEILELCREREDYSPLIRVIGRVFSSAEALVQSFRKVKQHTKEELKSLQAKDEDKDEDEKEKAACSAAAMEEDSEASSSRIGDSSQGDNNLQKLGPDDVSVDIDAIRRVYTRLLSNEKIETAFLNALVYLSPNVECDLTYHNVYSRDPNYLNLFIIVMENRNLHSPEYLEMALPLFCKAMSKLPLAAQGKLIRLWSKYNADQIRRMMETFQQLITYKVISNEFNSRNLVNDDDAIVAASKCLKMVYYANVVGGEVDTNHNEEDDEEPIPESSELTLQELLGEERRNKKGPRVDPLETELGVKTLDCRKPLIPFEEFINEPLNEVLEMDKDYTFFKVETENKFSFMTCPFILNAVTKNLGLYYDNRIRMYSERRITVLYSLVQGQQLNPYLRLKVRRDHIIDDALVRLEMIAMENPADLKKQLYVEFEGEQGVDEGGVSKEFFQLVVEEIFNPDIGMFTYDESTKLFWFNPSSFETEGQFTLIGIVLGLAIYNNCILDVHFPMVVYRKLMGKKGTFRDLGDSHPVLYQSLKDLLEYEGNVEDDMMITFQISQTDLFGNPMMYDLKENGDKIPITNENRKEFVNLYSDYILNKSVEKQFKAFRRGFHMVTNESPLKYLFRPEEIELLICGSRNLDFQALEETTEYDGGYTRDSVLIREFWEIVHSFTDEQKRLFLQFTTGTDRAPVGGLGKLKMIIAKNGPDTERLPTSHTCFNVLLLPEYSSKEKLKERLLKAITYAKGFGML(配列番号7)をコードする。
GDNFに基づく;
ATGAAGTTATGGGATGTCGTGGCTGTCTGCCTGGTGCTGCTCCACACCGCGTCCGCC(配列番号8)、
インスリンタンパク質からの;
ATGGCCCTGTGGATGCGCCTCCTGCCCCTGCTGGCGCTGCTGGCCCTCTGGGGACCTGACCCAGCCGCAGCC(配列番号9)、
またはIgKからの;
ATGGAGACAGACACACTCCTGCTATGGGTACTGCTGCTCTGGGTTCCAGGTTCCACTGGT(配列番号10)の、分泌シグナリングペプチドをコードする3つの遺伝子の1つに融合した。
HIV TAT配列;
YGRKKRRQRRR(配列番号5)、または
HIV TATk配列;
YARKAARQARA(配列番号11)、
のいずれかの細胞取り込みペプチド(細胞透過性ペプチド)に結合させた。
(配列番号12)。
(配列番号13)、タンパク質をコードする。
(配列番号14)
(配列番号12)。
Claims (12)
- サイトメガロウィルスチキンベータアクチンハイブリッドプロモーターまたはヒトユビキチンcプロモーターである転写開始配列、
前記転写開始配列の下流に配置された、配列番号12、配列番号13、配列番号15、配列番号7のcDNA、または配列番号14のcDNAである、UBE3A配列、
前記転写開始配列の下流に配置された、配列番号2、配列番号8、配列番号9、配列番号10、または配列番号3のcDNAである、分泌配列、および、
前記転写開始配列の下流に配置された、配列番号4、または配列番号5のcDNAである、細胞取り込み配列、を含むUBE3Aベクターであり、
前記UBE3Aベクターで遺伝子導入された細胞は、E6関連タンパク質を発現し、また、前記E6関連タンパク質を分泌し、
前記E6関連タンパク質が、E6関連タンパク質発現に欠陥がある脳細胞によって取り込まれる、
ことを特徴とするUBE3Aベクター。 - 前記転写開始配列の上流に配置されたサイトメガロウイルス最初期エンハンサー配列をさらに含むことを特徴とする、請求項1に記載のベクター。
- 前記UBE3A配列の下流に配置されたウッドチャック肝炎転写後調節エレメントをさらに含むことを特徴とする、請求項1に記載のベクター。
- 前記分泌配列は、前記UBE3A配列の上流に配置されていることを特徴とする、請求項1に記載のベクター。
- 前記細胞取り込み配列は、前記UBE3A配列の上流で前記分泌配列の下流に配置されていることを特徴とする、請求項1に記載のベクター。
- 転写開始配列を有する骨格プラスミドを用意することと、ここで、前記転写開始配列はサイトメガロウィルスチキンベータアクチンハイブリッドプロモーターまたはヒトユビキチンcプロモーターであり、
UBE3Aコンストラクトを作成することと、
前記UBE3Aコンストラクトを前記転写開始配列の下流に挿入することとを含み、
前記UBE3Aコンストラクトを作成することは、さらに、
配列番号12、配列番号13、配列番号15、配列番号7のcDNA、または配列番号14のcDNAである、UBE3A配列を用意することと、
配列番号2、配列番号8、配列番号9、配列番号10、または配列番号3のcDNAである、分泌配列を前記UBE3A配列に付加することと、
配列番号4、または配列番号5のcDNAである、細胞取り込み配列を前記UBE3A配列に付加することとを含む、
UBE3Aベクターの合成方法であり、
前記UBE3Aベクターで遺伝子導入された細胞は、E6関連タンパク質を発現し、また、前記E6関連タンパク質を分泌し、
前記E6関連タンパク質が、E6関連タンパク質発現に欠陥がある脳細胞によって取り込まれる、
ことを特徴とするUBE3Aベクターの合成方法。 - 前記ベクターを増幅宿主に挿入することと、
前記増幅宿主を抗生物質選択に晒すことと、ここで、前記骨格プラスミドは抗生物質耐性遺伝子を有し、
前記増幅宿主を、抗生物質選択を含む培地中で増殖させることと、
増殖した前記増幅宿主を回収することと、
前記ベクターを前記増幅宿主から単離することと、をさらに含むことを特徴とする、請求項6に記載の方法。 - 前記抗生物質耐性遺伝子は、アンピシリン耐性遺伝子であり、前記抗生物質選択は、アンピシリン選択であることを特徴とする、請求項7に記載の方法。
- UBE3A欠損疾患の治療のために使用される請求項1乃至5のいずれか一項に記載のUBE3Aベクターであって、
前記UBE3A欠損疾患は、アンジェルマン症候群、プラダ―・ウィリー症候群またはハンチントン病であることを特徴とするUBE3Aベクター。 - 前記UBE3A欠損疾患の治療が、前記UBE3Aベクターを脳に注射することである、請求項9に記載のUBE3Aベクター。
- 前記UBE3A欠損疾患の治療に使用される前記UBE3Aベクターの投与量が、5.55×1011から2.86×1012ゲノム/g脳質量、2.86×1012ゲノム/g脳質量、2.40×1012ゲノム/g脳質量、9.80×1011ゲノム/g脳質量または5.55×1011ゲノム/g脳質量であることを特徴とする、請求項9に記載のUBE3Aベクター。
- 前記UBE3Aベクターは、
前記転写開始配列の上流に配置されたサイトメガロウイルス最初期エンハンサー配列、
前記UBE3A配列の下流に配置されたウッドチャック肝炎転写後調節エレメント、
をさらに含み、
前記UBE3A配列は、配列番号12、配列番号13、または配列番号15であり、
前記細胞取り込み配列は、前記UBE3A配列の上流で前記転写開始配列の下流に配置され、前記細胞取り込み配列は、配列番号4、または配列番号5のcDNAであり、
前記分泌配列は、前記UBE3A配列の上流に配置され、前記分泌配列は、配列番号2、配列番号8、配列番号9、または配列番号10である
ことを特徴とする、請求項1に記載のベクター。
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JP2020528739A (ja) * | 2017-06-28 | 2020-10-01 | ユニヴァーシティ オブ サウス フロリダ | アンジェルマン症候群の遺伝子治療法のための改変ube3a遺伝子 |
CN110237257B (zh) * | 2018-03-09 | 2023-01-03 | 中国科学院脑科学与智能技术卓越创新中心 | Ube3a泛素化PP2A激活因子PTPA在治疗天使综合症和孤独症中的应用 |
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