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Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13\u201313.5 (E13\u201313.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.<\/jats:p>","DOI":"10.1093\/nar\/gkaa194","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T11:12:51Z","timestamp":1585653171000},"page":"5065-5080","source":"Crossref","is-referenced-by-count":39,"title":["Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction"],"prefix":"10.1093","volume":"48","author":[{"given":"Lingyan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Beth","family":"Kempton","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francine M","family":"Jodelka","sequence":"first","affiliation":[{"name":"Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9695-501X","authenticated-orcid":false,"given":"Alev M","family":"Brigande","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel A","family":"Dumont","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Rigo","sequence":"first","affiliation":[{"name":"Ionis Pharmaceuticals, Carlsbad, CA 92010 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J","family":"Lentz","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L","family":"Hastings","sequence":"first","affiliation":[{"name":"Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-4641","authenticated-orcid":false,"given":"John V","family":"Brigande","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Oregon Hearing Research Center, Oregon Health & Science University, Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,6]]},"reference":[{"key":"2020051611181883600_B1","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1136\/archdischild-2012-301786","article-title":"Neonatal hearing screening and intervention in resource-limited settings: an overview","volume":"97","author":"Olusanya","year":"2012","journal-title":"Arch. 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