TY - JOUR
T1 - Improved TMC1 gene therapy restores hearing and balance in mice with genetic inner ear disorders
AU - Nist-Lund, Carl A.
AU - Pan, Bifeng
AU - Patterson, Amy
AU - Asai, Yukako
AU - Chen, Tianwen
AU - Zhou, Wu
AU - Zhu, Hong
AU - Romero, Sandra
AU - Resnik, Jennifer
AU - Polley, Daniel B.
AU - Géléoc, Gwenaelle S.
AU - Holt, Jeffrey R.
N1 - Funding Information:
The authors would like to thank the BCH Viral Core and Neurobehavioral Core (BCH IDDRC, 1U54HD090255). Work in the Holt/Géléoc Lab was supported by NIDCD grants R01 DC013521 (J.R.H.) and R01 DC008853 (G.S.G.) and the Bertarelli Foundation Program and Program in Translational Neuroscience and Neuroengineering. J.R. was supported by a grant from the Hearing Health Foundation. SR was supported by the Bertarelli Program in Translational Neuroscience and Neuroengineering. Work in the Polley lab was supported by NIDCD grant R01 DC009836. Work in the Zhu and Zhou labs was supported by NIDCD grants R01DC012060 (H.Z.), R01DC014930 (W.Z.) and R21EY025550 (W.Z.).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85060396991&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-08264-w
DO - 10.1038/s41467-018-08264-w
M3 - Article
AN - SCOPUS:85060396991
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 236
ER -