Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders

Carl A. Nist-Lund, Bifeng Pan, Amy Patterson, Yukako Asai, Tianwen Chen, Wu Zhou, Hong Zhu, Sandra Romero, Jennifer Resnik, Daniel B. Polley, Gwenaelle S. Géléoc, Jeffrey R. Holt

Research output: Contribution to journalArticlepeer-review

92 Scopus citations


Fifty percent of inner ear disorders are caused by genetic mutations. To develop treatments for genetic inner ear disorders, we designed gene replacement therapies using synthetic adeno-associated viral vectors to deliver the coding sequence for Transmembrane Channel-Like (Tmc) 1 or 2 into sensory hair cells of mice with hearing and balance deficits due to mutations in Tmc1 and closely related Tmc2. Here we report restoration of function in inner and outer hair cells, enhanced hair cell survival, restoration of cochlear and vestibular function, restoration of neural responses in auditory cortex and recovery of behavioral responses to auditory and vestibular stimulation. Secondarily, we find that inner ear Tmc gene therapy restores breeding efficiency, litter survival and normal growth rates in mouse models of genetic inner ear dysfunction. Although challenges remain, the data suggest that Tmc gene therapy may be well suited for further development and perhaps translation to clinical application.

Original languageEnglish
Article number236
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2019
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)


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