{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T11:50:33Z","timestamp":1790769033133,"version":"4.1.0"},"reference-count":51,"publisher":"SAGE Publications","issue":"1-2","license":[{"start":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T00:00:00Z","timestamp":1640995200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Huntington's disease (HD) is a devastating, autosomal dominant neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Inactivation of the mutant allele by clustered regularly interspaced short palindromic repeats (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 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.<\/jats:p>","DOI":"10.1089\/hum.2020.323","type":"journal-article","created":{"date-parts":[[2021,8,11]],"date-time":"2021-08-11T02:37:04Z","timestamp":1628649424000},"page":"25-36","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":18,"title":["Allele-Specific Knockdown of Mutant Huntingtin Protein via Editing at Coding Region Single Nucleotide Polymorphism Heterozygosities"],"prefix":"10.1177","volume":"33","author":[{"given":"Sarah R.","family":"Oikemus","sequence":"first","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith L.","family":"Pfister","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Sapp","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn O.","family":"Chase","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori A.","family":"Kennington","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Hudgens","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihua Julie","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksh","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric O.","family":"Mick","sequence":"additional","affiliation":[{"name":"Department of Population and Quantitative Health Sciences, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sena-Esteves","sequence":"additional","affiliation":[{"name":"Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scot A.","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"},{"name":"Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"DiFiglia","sequence":"additional","affiliation":[{"name":"Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Charlestown, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil","family":"Aronin","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"},{"name":"RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7703-4872","authenticated-orcid":false,"given":"Michael H.","family":"Brodsky","sequence":"additional","affiliation":[{"name":"Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2022,1,17]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90585-E"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90106-X"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90346-1"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45130"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206506109"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0478-3"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2012.05.009"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.199"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-160215"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2009.03.030"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0501507102"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-019-0205-0"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2018.06.021"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/gt.2017.71"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2013.200"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1089\/dna.2019.5188"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2015.2"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.05.010"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92087"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.075"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.3233\/JHD-170235"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.12.069"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/81593"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2443-18.2018"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4699-13.2014"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2016.11.010"},{"key":"e_1_3_6_28_2","first-page":"4566","article-title":"Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR\/Cas9","volume":"25","author":"Shin JW","year":"2016","unstructured":"Shin JW, , Kim KH, , Chao MJ, et al. Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR\/Cas9. Hum Mol Genet, 2016; 25:4566\u20134576.","journal-title":"Hum Mol Genet"},{"key":"e_1_3_6_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0344-3"},{"key":"e_1_3_6_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12449-2"},{"key":"e_1_3_6_31_2","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2018.193"},{"key":"e_1_3_6_32_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genet-111212-133424"},{"key":"e_1_3_6_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0108424"},{"key":"e_1_3_6_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/mtna.2013.12"},{"key":"e_1_3_6_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231143"},{"key":"e_1_3_6_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2159"},{"key":"e_1_3_6_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2004.08.017"},{"key":"e_1_3_6_38_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0857-08.2008"},{"key":"e_1_3_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80764-3"},{"key":"e_1_3_6_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1095-155"},{"key":"e_1_3_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.014"},{"key":"e_1_3_6_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2015.231"},{"key":"e_1_3_6_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3583"},{"key":"e_1_3_6_44_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-9170-9_3"},{"key":"e_1_3_6_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.125"},{"key":"e_1_3_6_46_2","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/els051"},{"key":"e_1_3_6_47_2","doi-asserted-by":"publisher","DOI":"10.1039\/c1lc20561g"},{"key":"e_1_3_6_48_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac202028g"},{"key":"e_1_3_6_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.07.009"},{"key":"e_1_3_6_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.03.004"},{"key":"e_1_3_6_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0137-0"},{"key":"e_1_3_6_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0565-5"}],"container-title":["Human Gene Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/hum.2020.323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2020.323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/hum.2020.323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:56:06Z","timestamp":1777449366000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1089\/hum.2020.323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1]]},"references-count":51,"journal-issue":{"issue":"1-2","published-print":{"date-parts":[[2022,1]]}},"alternative-id":["10.1089\/hum.2020.323"],"URL":"https:\/\/doi.org\/10.1089\/hum.2020.323","relation":{},"ISSN":["1043-0342","1557-7422"],"issn-type":[{"value":"1043-0342","type":"print"},{"value":"1557-7422","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1]]}}}