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Currently, there is no curative or disease\u2010slowing treatment for these disorders, but their monogenic inheritance has informed rationales for development of gene therapy strategies. In fact, RNA interference strategies have shown promising findings in cellular and\/or animal models of SCA1, SCA3, SCA6, and SCA7. In addition, antisense oligonucleotide therapy has provided encouraging proofs of concept in models of SCA1, SCA2, SCA3, and SCA7, but they have not yet progressed to clinical trials. On the contrary, the gene editing strategies, such as the clustered regularly interspaced short palindromic repeat (CRISPR\/Cas9), have been introduced to a limited extent in these disorders. In this article, we review the available literature about gene therapy in polyglutamine SCAs and discuss the main technological and ethical challenges toward the prospect of their use in future clinical trials. Although antisense oligonucleotide therapies are further along the path to clinical phases, the recent failure of three clinical trials in Huntington's disease may delay their utilization for polyglutamine SCAs, but they offer lessons that could optimize the likelihood of success in potential future clinical studies. \u00a9 2021 International Parkinson and Movement Disorder Society<\/jats:p>","DOI":"10.1002\/mds.28819","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T13:52:20Z","timestamp":1633873940000},"page":"2731-2744","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Gene Therapy for Polyglutamine Spinocerebellar Ataxias: Advances, Challenges, and 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