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dc.contributor.authorWang, Dan
dc.contributor.authorMou, Haiwei
dc.contributor.authorLi, Shaoyong
dc.contributor.authorLi, Yingxiang
dc.contributor.authorHough, Soren
dc.contributor.authorTran, Karen
dc.contributor.authorLi, Jia
dc.contributor.authorYin, Hao
dc.contributor.authorAnderson, Daniel G.
dc.contributor.authorSontheimer, Erik J.
dc.contributor.authorWeng, Zhiping
dc.contributor.authorGao, Guangping
dc.contributor.authorXue, Wen
dc.date2022-08-11T08:07:59.000
dc.date.accessioned2022-08-23T15:38:27Z
dc.date.available2022-08-23T15:38:27Z
dc.date.issued2015-07-01
dc.date.submitted2016-01-07
dc.identifier.citationHum Gene Ther. 2015 Jul;26(7):432-42. doi: 10.1089/hum.2015.087. <a href="http://dx.doi.org/10.1089/hum.2015.087">Link to article on publisher's site</a>
dc.identifier.issn1043-0342 (Linking)
dc.identifier.doi10.1089/hum.2015.087
dc.identifier.pmid26086867
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25937
dc.description.abstractCRISPR/Cas9 derived from the bacterial adaptive immunity pathway is a powerful tool for genome editing, but the safety profiles of in vivo delivered Cas9 (including host immune responses to the bacterial Cas9 protein) have not been comprehensively investigated in model organisms. Nonalcoholic steatohepatitis (NASH) is a prevalent human liver disease characterized by excessive fat accumulation in the liver. In this study, we used adenovirus (Ad) vector to deliver a Streptococcus pyogenes-derived Cas9 system (SpCas9) targeting Pten, a gene involved in NASH and a negative regulator of the PI3K-AKT pathway, in mouse liver. We found that the Ad vector mediated efficient Pten gene editing even in the presence of typical Ad vector-associated immunotoxicity in the liver. Four months after vector infusion, mice receiving the Pten gene-editing Ad vector showed massive hepatomegaly and features of NASH, consistent with the phenotypes following Cre-loxP-induced Pten deficiency in mouse liver. We also detected induction of humoral immunity against SpCas9 and the potential presence of an SpCas9-specific cellular immune response. Our findings provide a strategy to model human liver diseases in mice and highlight the importance considering Cas9-specific immune responses in future translational studies involving in vivo delivery of CRISPR/Cas9.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=26086867&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1089/hum.2015.087
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectBioinformatics
dc.subjectComputational Biology
dc.subjectImmunity
dc.subjectImmunoprophylaxis and Therapy
dc.subjectIntegrative Biology
dc.subjectSystems Biology
dc.titleAdenovirus-Mediated Somatic Genome Editing of Pten by CRISPR/Cas9 in Mouse Liver in Spite of Cas9-Specific Immune Responses
dc.typeJournal Article
dc.source.journaltitleHuman gene therapy
dc.source.volume26
dc.source.issue7
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/78
dc.identifier.contextkey7992046
html.description.abstract<p>CRISPR/Cas9 derived from the bacterial adaptive immunity pathway is a powerful tool for genome editing, but the safety profiles of in vivo delivered Cas9 (including host immune responses to the bacterial Cas9 protein) have not been comprehensively investigated in model organisms. Nonalcoholic steatohepatitis (NASH) is a prevalent human liver disease characterized by excessive fat accumulation in the liver. In this study, we used adenovirus (Ad) vector to deliver a Streptococcus pyogenes-derived Cas9 system (SpCas9) targeting Pten, a gene involved in NASH and a negative regulator of the PI3K-AKT pathway, in mouse liver. We found that the Ad vector mediated efficient Pten gene editing even in the presence of typical Ad vector-associated immunotoxicity in the liver. Four months after vector infusion, mice receiving the Pten gene-editing Ad vector showed massive hepatomegaly and features of NASH, consistent with the phenotypes following Cre-loxP-induced Pten deficiency in mouse liver. We also detected induction of humoral immunity against SpCas9 and the potential presence of an SpCas9-specific cellular immune response. Our findings provide a strategy to model human liver diseases in mice and highlight the importance considering Cas9-specific immune responses in future translational studies involving in vivo delivery of CRISPR/Cas9.</p>
dc.identifier.submissionpathbioinformatics_pubs/78
dc.contributor.departmentGene Therapy Center
dc.contributor.departmentRNA Therapeutics Institute
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Bioinformatics and Integrative Biology
dc.source.pages432-42


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