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  4. Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
 
research article

Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice

Wu, Jason
•
Solanes, Paola  
•
Nist-Lund, Carl
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March 3, 2021
Molecular Therapy

AAV-mediated gene therapy is a promising approach for treating genetic hearing loss. Replacement or editing of the Tmc1 gene, encoding hair cell mechanosensory ion channels, is effective for hearing restoration in mice with some limitations. Efficient rescue of outer hair cell function and lack of hearing recovery with later-stage treatment remain issues to be solved. Exogenous genes delivered with the adeno-associated virus (AAV)9-PHP.B capsid via the utricle transduce both inner and outer hair cells of the mouse cochlea with high efficacy. Here, we demonstrate that AAV9-PHP.B gene therapy can promote hair cell survival and successfully rescues hearing in three distinct mouse models of hearing loss. Tmc1 replacement with AAV9-PHP.B in a Tmc1 knockout mouse rescues hearing and promotes hair cell survival with equal efficacy in inner and outer hair cells. The same treatment in a recessive Tmc1 hearing-loss model, Baringo, partially recovers hearing even with later-stage treatment. Finally, dual delivery of Streptococcus pyogenes Cas9 (SpCas9) and guide RNA (gRNA) in separate AAV9-PHP.B vectors selectively disrupts a dominant Tmc1 allele and preserves hearing in Beethoven mice, a model of dominant, progressive hearing loss. Tmc1-targeted gene therapies using single or dual AAV9-PHP.B vectors offer potent and versatile approaches for treating dominant and recessive deafness.

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Type
research article
DOI
10.1016/j.ymthe.2020.11.016
Web of Science ID

WOS:000632042500012

Author(s)
Wu, Jason
Solanes, Paola  
Nist-Lund, Carl
Spataro, Sofia  
Shubina-Oleinik, Olga
Marcovich, Irina
Goldberg, Hannah
Schneider, Bernard L.
Holt, Jeffrey R.
Date Issued

2021-03-03

Publisher

CELL PRESS

Published in
Molecular Therapy
Volume

29

Issue

3

Start page

973

End page

988

Subjects

Biotechnology & Applied Microbiology

•

Genetics & Heredity

•

Medicine, Research & Experimental

•

Research & Experimental Medicine

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LEN  
Available on Infoscience
May 22, 2021
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/178255
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