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Since the reduction of pathogenic mutant <jats:italic>HTT<\/jats:italic> messenger RNA is therapeutic, we developed a mutant allele-sensitive CAG<jats:sup>EX<\/jats:sup> RNA-targeting CRISPR\u2013Cas13d system (Cas13d\u2013CAG<jats:sup>EX<\/jats:sup>) that eliminates toxic CAG<jats:sup>EX<\/jats:sup> RNA in fibroblasts derived from patients with HD and induced pluripotent stem cell-derived neurons. We show that intrastriatal delivery of Cas13d\u2013CAG<jats:sup>EX<\/jats:sup> via an adeno-associated viral vector selectively reduces mutant <jats:italic>HTT<\/jats:italic> mRNA and protein levels in the striatum of heterozygous zQ175 mice, a model of HD. This also led to improved motor coordination, attenuated striatal atrophy and reduction of mutant HTT protein aggregates. These phenotypic improvements lasted for at least eight months without adverse effects and with minimal off-target transcriptomic effects. Taken together, we demonstrate proof of principle of an RNA-targeting CRISPR\u2013Cas13d system as a therapeutic approach for HD, a strategy with implications for the treatment of other dominantly inherited disorders.<\/jats:p>","DOI":"10.1038\/s41593-022-01207-1","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T17:06:28Z","timestamp":1670864788000},"page":"27-38","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":108,"title":["An RNA-targeting CRISPR\u2013Cas13d system alleviates disease-related phenotypes in Huntington\u2019s disease models"],"prefix":"10.1038","volume":"26","author":[{"given":"Kathryn H.","family":"Morelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7815-522X","authenticated-orcid":false,"given":"Qian","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4758-4800","authenticated-orcid":false,"given":"Maya L.","family":"Gosztyla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongshuai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minmin","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuangchuang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5570-6233","authenticated-orcid":false,"given":"Jiaxu","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2427-7912","authenticated-orcid":false,"given":"Ryan J.","family":"Marina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9194-6245","authenticated-orcid":false,"given":"Krysten L.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9676-6507","authenticated-orcid":false,"given":"Megan Y.","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5617-0568","authenticated-orcid":false,"given":"Allison","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2136-4420","authenticated-orcid":false,"given":"Charlene","family":"Smith-Geater","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-9514","authenticated-orcid":false,"given":"Leslie M.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-6308","authenticated-orcid":false,"given":"Wenzhen","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0799-6037","authenticated-orcid":false,"given":"Gene W.","family":"Yeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,12]]},"reference":[{"key":"1207_CR1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/B978-0-444-63233-3.00009-9","volume":"147","author":"H Paulson","year":"2018","unstructured":"Paulson, H. 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