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dc.contributor.authorOikemus, Sarah
dc.contributor.authorPfister, Edith L.
dc.contributor.authorSapp, Ellen
dc.contributor.authorChase, Kathryn O.
dc.contributor.authorKennington, Lori A.
dc.contributor.authorHudgens, Edward
dc.contributor.authorMiller, Rachael
dc.contributor.authorZhu, Lihua Julie
dc.contributor.authorChaudhary, Akanksh
dc.contributor.authorMick, Eric O.
dc.contributor.authorSena-Esteves, Miguel
dc.contributor.authorWolfe, Scot A.
dc.contributor.authorDiFiglia, Marian
dc.contributor.authorAronin, Neil
dc.contributor.authorBrodsky, Michael H.
dc.date2022-08-11T08:10:37.000
dc.date.accessioned2022-08-23T17:14:24Z
dc.date.available2022-08-23T17:14:24Z
dc.date.issued2021-08-10
dc.date.submitted2021-10-18
dc.identifier.citation<p>Oikemus SR, Pfister E, Sapp E, Chase KO, Kennington LA, Hudgens E, Miller R, Zhu LJ, Chaudhary A, Mick EO, Sena-Esteves M, Wolfe SA, DiFiglia M, Aronin N, Brodsky MH. Allele-specific knockdown of mutant HTT protein via editing at coding region SNP heterozygosities. Hum Gene Ther. 2021 Aug 10. doi: 10.1089/hum.2020.323. Epub ahead of print. PMID: 34376056. <a href="https://doi.org/10.1089/hum.2020.323">Link to article on publisher's site</a></p>
dc.identifier.issn1043-0342 (Linking)
dc.identifier.doi10.1089/hum.2020.323
dc.identifier.pmid34376056
dc.identifier.urihttp://hdl.handle.net/20.500.14038/46946
dc.description.abstractHuntington's disease (HD) is a devasting, autosomal dominant neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene. Inactivation of the mutant allele by CRISPR-Cas9 based gene editing offers a possible therapeutic approach for this disease, but permanent disruption of normal HTT function might compromise adult neuronal function. Here, we use a novel HD mouse model to examine allele-specific editing of mutant HTT (mHTT), with a BAC97 transgene expressing mHTT and a YAC18 transgene expressing normal HTT. We achieve allele-specific inactivation of HTT by targeting a protein coding sequence containing a common, heterozygous single nucleotide polymorphism (SNP). The outcome is a marked and allele-selective reduction of mutant HTT (mHTT) protein in a mouse model of HD. Expression of a single CRISPR-Cas9 nuclease in neurons generated a high frequency of mutations in the targeted HD allele that included both small insertion/deletion (InDel) mutations and viral vector insertions. Thus, allele-specific targeting of InDel and insertion mutations to heterozygous coding region SNPs provides a feasible approach to inactivate autosomal dominant mutations that cause genetic disease.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=34376056&dopt=Abstract">Link to Article in PubMed</a></p>
dc.relation.urlhttps://doi.org/10.1089/hum.2020.323
dc.rights© Mary Ann Liebert, Inc. 2021. PDF of authors' peer-reviewed accepted manuscript posted with a 12-month embargo as allowed by the publisher's self-archiving policy at https://home.liebertpub.com/authors/policies/152#self-archiving. Final publication is available from Mary Ann Liebert, Inc., publishers https://doi.org/10.1089/hum.2020.323.
dc.subjectHuntington’s Disease
dc.subjectGene Editing
dc.subjectSingle Nucleotide Polymorphism
dc.subjectUMCCTS funding
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectGenetics and Genomics
dc.subjectNervous System Diseases
dc.subjectNeuroscience and Neurobiology
dc.subjectTherapeutics
dc.titleAllele-specific knockdown of mutant HTT protein via editing at coding region SNP heterozygosities
dc.typeAccepted Manuscript
dc.source.journaltitleHuman gene therapy
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2430&amp;context=qhs_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/qhs_pp/1426
dc.legacy.embargo2022-08-10T00:00:00-07:00
dc.identifier.contextkey25463685
refterms.dateFOA2022-08-23T17:14:24Z
html.description.abstract<p>Huntington's disease (HD) is a devasting, autosomal dominant neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene. Inactivation of the mutant allele by CRISPR-Cas9 based gene editing offers a possible therapeutic approach for this disease, but permanent disruption of normal HTT function might compromise adult neuronal function. Here, we use a novel HD mouse model to examine allele-specific editing of mutant HTT (mHTT), with a BAC97 transgene expressing mHTT and a YAC18 transgene expressing normal HTT. We achieve allele-specific inactivation of HTT by targeting a protein coding sequence containing a common, heterozygous single nucleotide polymorphism (SNP). The outcome is a marked and allele-selective reduction of mutant HTT (mHTT) protein in a mouse model of HD. Expression of a single CRISPR-Cas9 nuclease in neurons generated a high frequency of mutations in the targeted HD allele that included both small insertion/deletion (InDel) mutations and viral vector insertions. Thus, allele-specific targeting of InDel and insertion mutations to heterozygous coding region SNPs provides a feasible approach to inactivate autosomal dominant mutations that cause genetic disease.</p>
dc.identifier.submissionpathqhs_pp/1426
dc.contributor.departmentGraduate School of Biomedical Sciences
dc.contributor.departmentHorae Gene Therapy Center
dc.contributor.departmentPopulation and Quantitative Health Sciences
dc.contributor.departmentMedicine
dc.contributor.departmentUMass Chan Analytics
dc.contributor.departmentBiostatistics and Health Services Research
dc.contributor.departmentMolecular, Cell and Cancer Biology


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