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Alliance"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:p>Hearing loss is the most common sensory deficit, of which genetic etiologies are a frequent cause. Dominant and recessive mutations in<jats:italic>TMC1<\/jats:italic>, a gene encoding the pore-forming subunit of the hair cell mechanotransduction channel, cause DFNA36 and DFNB7\/11, respectively, accounting for \u223c2% of genetic hearing loss. Previous work has established the efficacy of mutation-targeted RNAi in treatment of murine models of autosomal dominant non-syndromic deafness. However, application of such approaches is limited by the infeasibility of development and validation of novel constructs for each variant. We developed an allele-non-specific approach consisting of mutation-agnostic RNAi suppression of both mutant and WT alleles, co-delivered with a knockdown-resistant engineered WT allele with or without the use of woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) to augment transgene expression. This therapeutic construct was delivered into the mature murine model of DFNA36 with an AAV vector and achieved robust hair cell and auditory brainstem response preservation. However, WPRE-enhanced<jats:italic>Tmc1<\/jats:italic>expression resulted in inferior outcomes, suggesting a role for gene dosage optimization in future<jats:italic>TMC1<\/jats:italic>gene therapy development.<\/jats:p>","DOI":"10.26508\/lsa.202201592","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T16:35:15Z","timestamp":1672158915000},"page":"e202201592","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":11,"title":["Mutation-agnostic RNA interference with engineered replacement rescues<i>Tmc1<\/i>-related hearing loss"],"prefix":"10.26508","volume":"6","author":[{"given":"Yoichiro","family":"Iwasa","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Shinshu University School of Medicine, Matsumoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7278-8728","authenticated-orcid":true,"given":"Miles J","family":"Klimara","sequence":"additional","affiliation":[{"name":"Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology \u2013 Head and Neck Surgery, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9601-7496","authenticated-orcid":true,"given":"Hidekane","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8539-0049","authenticated-orcid":false,"given":"William D","family":"Walls","sequence":"additional","affiliation":[{"name":"Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology \u2013 Head and Neck Surgery, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryotaro","family":"Omichi","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology \u2013 Head and Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody A","family":"West","sequence":"additional","affiliation":[{"name":"Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology \u2013 Head and Neck Surgery, University of Iowa, Iowa City, IA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji B","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology Head and Neck Surgery, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul T","family":"Ranum","sequence":"additional","affiliation":[{"name":"Raymond G. 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