Allele-specific knockdown of mutant HTT protein via editing at coding region SNP heterozygosities
dc.contributor.author | Oikemus, Sarah | |
dc.contributor.author | Pfister, Edith L. | |
dc.contributor.author | Sapp, Ellen | |
dc.contributor.author | Chase, Kathryn O. | |
dc.contributor.author | Kennington, Lori A. | |
dc.contributor.author | Hudgens, Edward | |
dc.contributor.author | Miller, Rachael | |
dc.contributor.author | Zhu, Lihua Julie | |
dc.contributor.author | Chaudhary, Akanksh | |
dc.contributor.author | Mick, Eric O. | |
dc.contributor.author | Sena-Esteves, Miguel | |
dc.contributor.author | Wolfe, Scot A. | |
dc.contributor.author | DiFiglia, Marian | |
dc.contributor.author | Aronin, Neil | |
dc.contributor.author | Brodsky, Michael H. | |
dc.date | 2022-08-11T08:10:37.000 | |
dc.date.accessioned | 2022-08-23T17:14:24Z | |
dc.date.available | 2022-08-23T17:14:24Z | |
dc.date.issued | 2021-08-10 | |
dc.date.submitted | 2021-10-18 | |
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.issn | 1043-0342 (Linking) | |
dc.identifier.doi | 10.1089/hum.2020.323 | |
dc.identifier.pmid | 34376056 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/46946 | |
dc.description.abstract | 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. | |
dc.language.iso | en_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.url | https://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.subject | Huntington’s Disease | |
dc.subject | Gene Editing | |
dc.subject | Single Nucleotide Polymorphism | |
dc.subject | UMCCTS funding | |
dc.subject | Amino Acids, Peptides, and Proteins | |
dc.subject | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | |
dc.subject | Genetics and Genomics | |
dc.subject | Nervous System Diseases | |
dc.subject | Neuroscience and Neurobiology | |
dc.subject | Therapeutics | |
dc.title | Allele-specific knockdown of mutant HTT protein via editing at coding region SNP heterozygosities | |
dc.type | Accepted Manuscript | |
dc.source.journaltitle | Human gene therapy | |
dc.identifier.legacyfulltext | https://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=2430&context=qhs_pp&unstamped=1 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/qhs_pp/1426 | |
dc.legacy.embargo | 2022-08-10T00:00:00-07:00 | |
dc.identifier.contextkey | 25463685 | |
refterms.dateFOA | 2022-08-23T17:14:24Z | |
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.submissionpath | qhs_pp/1426 | |
dc.contributor.department | Graduate School of Biomedical Sciences | |
dc.contributor.department | Horae Gene Therapy Center | |
dc.contributor.department | Population and Quantitative Health Sciences | |
dc.contributor.department | Medicine | |
dc.contributor.department | UMass Chan Analytics | |
dc.contributor.department | Biostatistics and Health Services Research | |
dc.contributor.department | Molecular, Cell and Cancer Biology |