Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction

Lingyan Wang, J. Beth Kempton, Han Jiang, Francine M. Jodelka, Alev M. Brigande, Rachel A. Dumont, Frank Rigo, Jennifer J. Lentz, Michelle L. Hastings, John V. Brigande

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. 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 13-13.5 (E13-13.5) 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.

Original languageEnglish (US)
Pages (from-to)5065-5080
Number of pages16
JournalNucleic acids research
Issue number9
StatePublished - May 21 2020

ASJC Scopus subject areas

  • Genetics


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