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(polyQ)-encoding CAG repeat expansions represent a common disease-causing mutation responsible for several dominant spinocerebellar ataxias (SCAs). PolyQ-expanded SCA proteins are toxic for cerebellar neurons, with Purkinje cells (PCs) being the most vulnerable. RNA interference (RNAi) reagents targeting transcripts with expanded CAG reduce the level of various mutant SCA proteins in an allele-selective manner in vitro and represent promising universal tools for treating multiple CAG\/polyQ SCAs. However, it remains unclear whether the therapeutic targeting of CAG expansion can be achieved in vivo and if it can ameliorate cerebellar functions. Here, using a mouse model of SCA7 expressing a mutant Atxn7 allele with 140 CAGs, we examined the efficacy of short hairpin RNAs (shRNAs) targeting CAG repeats expressed from PHP.eB adeno-associated virus vectors (AAVs), which were introduced into the brain via intravascular injection. We demonstrated that shRNAs carrying various mismatches with the CAG target sequence reduced the level of polyQ-expanded ATXN7 in the cerebellum, albeit with varying degrees of allele selectivity and safety profile. An shRNA named A4 potently reduced the level of polyQ-expanded ATXN7, with no effect on normal ATXN7 levels and no adverse side effects. Furthermore, A4 shRNA treatment improved a range of motor and behavioral parameters 23 weeks after AAV injection and attenuated the disease burden of PCs by preventing the downregulation of several PC-type-specific genes. Our results show the feasibility of the selective targeting of CAG expansion in the cerebellum using a blood\u2013brain barrier-permeable vector to attenuate the disease phenotype in an SCA mouse model. Our study represents a significant advancement in developing CAG-targeting strategies as a potential therapy for SCA7 and possibly other CAG\/polyQ SCAs.<\/jats:p>","DOI":"10.3390\/ijms25084354","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T11:53:53Z","timestamp":1713182033000},"page":"4354","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["AAV-Mediated CAG-Targeting Selectively Reduces Polyglutamine-Expanded Protein and Attenuates Disease Phenotypes in a Spinocerebellar Ataxia Mouse Model"],"prefix":"10.3390","volume":"25","author":[{"given":"Anna","family":"Niewiadomska-Cimicka","sequence":"first","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, INSERM U1258, CNRS UMR7104, University of Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0332-3417","authenticated-orcid":false,"given":"Lorraine","family":"Fievet","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, INSERM U1258, CNRS UMR7104, University of Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Surdyka","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewelina","family":"Jesion","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-3814","authenticated-orcid":false,"given":"C\u00e9line","family":"Keime","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, INSERM U1258, CNRS UMR7104, University of Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6669-9676","authenticated-orcid":false,"given":"Elisabeth","family":"Singer","sequence":"additional","affiliation":[{"name":"Centre for Rare Diseases (ZSE), University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany"},{"name":"Department of Human Genetics, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Eisenmann","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, INSERM U1258, CNRS UMR7104, University of Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaneta","family":"Kalinowska-Poska","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6139-788X","authenticated-orcid":false,"given":"Hoa Huu Phuc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7829-1926","authenticated-orcid":false,"given":"Agnieszka","family":"Fiszer","sequence":"additional","affiliation":[{"name":"Department of Medical Biotechnology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12\/14, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3961-4635","authenticated-orcid":false,"given":"Maciej","family":"Figiel","sequence":"additional","affiliation":[{"name":"Department of Molecular Neurobiology, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61-704 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7230-4810","authenticated-orcid":false,"given":"Yvon","family":"Trottier","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular and Cellular Biology, INSERM U1258, CNRS UMR7104, University of Strasbourg, 67404 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/s41572-019-0074-3","article-title":"Spinocerebellar ataxia","volume":"5","author":"Klockgether","year":"2019","journal-title":"Nat. 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