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

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 h...

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Autores principales: Wu, Jason, Solanes, Paola, Nist-Lund, Carl, Spataro, Sofia, Shubina-Oleinik, Olga, Marcovich, Irina, Goldberg, Hannah, Schneider, Bernard L., Holt, Jeffrey R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934577/
https://www.ncbi.nlm.nih.gov/pubmed/33212302
http://dx.doi.org/10.1016/j.ymthe.2020.11.016
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author Wu, Jason
Solanes, Paola
Nist-Lund, Carl
Spataro, Sofia
Shubina-Oleinik, Olga
Marcovich, Irina
Goldberg, Hannah
Schneider, Bernard L.
Holt, Jeffrey R.
author_facet Wu, Jason
Solanes, Paola
Nist-Lund, Carl
Spataro, Sofia
Shubina-Oleinik, Olga
Marcovich, Irina
Goldberg, Hannah
Schneider, Bernard L.
Holt, Jeffrey R.
author_sort Wu, Jason
collection PubMed
description 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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spelling pubmed-79345772022-03-03 Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice Wu, Jason Solanes, Paola Nist-Lund, Carl Spataro, Sofia Shubina-Oleinik, Olga Marcovich, Irina Goldberg, Hannah Schneider, Bernard L. Holt, Jeffrey R. Mol Ther Original Article 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. American Society of Gene & Cell Therapy 2021-03-03 2020-11-17 /pmc/articles/PMC7934577/ /pubmed/33212302 http://dx.doi.org/10.1016/j.ymthe.2020.11.016 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Wu, Jason
Solanes, Paola
Nist-Lund, Carl
Spataro, Sofia
Shubina-Oleinik, Olga
Marcovich, Irina
Goldberg, Hannah
Schneider, Bernard L.
Holt, Jeffrey R.
Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title_full Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title_fullStr Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title_full_unstemmed Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title_short Single and Dual Vector Gene Therapy with AAV9-PHP.B Rescues Hearing in Tmc1 Mutant Mice
title_sort single and dual vector gene therapy with aav9-php.b rescues hearing in tmc1 mutant mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934577/
https://www.ncbi.nlm.nih.gov/pubmed/33212302
http://dx.doi.org/10.1016/j.ymthe.2020.11.016
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