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 and Jeffrey R. Holt ()
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Carl A. Nist-Lund: Boston Children’s Hospital
Bifeng Pan: Boston Children’s Hospital
Amy Patterson: Boston Children’s Hospital
Yukako Asai: Boston Children’s Hospital
Tianwen Chen: University of Mississippi Medical Center
Wu Zhou: University of Mississippi Medical Center
Hong Zhu: University of Mississippi Medical Center
Sandra Romero: Massachusetts Eye and Ear Infirmary
Jennifer Resnik: Harvard Medical School
Daniel B. Polley: Harvard Medical School
Gwenaelle S. Géléoc: Boston Children’s Hospital
Jeffrey R. Holt: Boston Children’s Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-018-08264-w

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