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Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate
Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in bot...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297893/ https://www.ncbi.nlm.nih.gov/pubmed/30581889 http://dx.doi.org/10.1016/j.omtm.2018.11.003 |
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author | György, Bence Meijer, Elise J. Ivanchenko, Maryna V. Tenneson, Kelly Emond, Frederick Hanlon, Killian S. Indzhykulian, Artur A. Volak, Adrienn Karavitaki, K. Domenica Tamvakologos, Panos I. Vezina, Mark Berezovskii, Vladimir K. Born, Richard T. O’Brien, Maureen Lafond, Jean-François Arsenijevic, Yvan Kenna, Margaret A. Maguire, Casey A. Corey, David P. |
author_facet | György, Bence Meijer, Elise J. Ivanchenko, Maryna V. Tenneson, Kelly Emond, Frederick Hanlon, Killian S. Indzhykulian, Artur A. Volak, Adrienn Karavitaki, K. Domenica Tamvakologos, Panos I. Vezina, Mark Berezovskii, Vladimir K. Born, Richard T. O’Brien, Maureen Lafond, Jean-François Arsenijevic, Yvan Kenna, Margaret A. Maguire, Casey A. Corey, David P. |
author_sort | György, Bence |
collection | PubMed |
description | Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector. |
format | Online Article Text |
id | pubmed-6297893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-62978932018-12-21 Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate György, Bence Meijer, Elise J. Ivanchenko, Maryna V. Tenneson, Kelly Emond, Frederick Hanlon, Killian S. Indzhykulian, Artur A. Volak, Adrienn Karavitaki, K. Domenica Tamvakologos, Panos I. Vezina, Mark Berezovskii, Vladimir K. Born, Richard T. O’Brien, Maureen Lafond, Jean-François Arsenijevic, Yvan Kenna, Margaret A. Maguire, Casey A. Corey, David P. Mol Ther Methods Clin Dev Article Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector. American Society of Gene & Cell Therapy 2018-11-20 /pmc/articles/PMC6297893/ /pubmed/30581889 http://dx.doi.org/10.1016/j.omtm.2018.11.003 Text en © 2018 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 | Article György, Bence Meijer, Elise J. Ivanchenko, Maryna V. Tenneson, Kelly Emond, Frederick Hanlon, Killian S. Indzhykulian, Artur A. Volak, Adrienn Karavitaki, K. Domenica Tamvakologos, Panos I. Vezina, Mark Berezovskii, Vladimir K. Born, Richard T. O’Brien, Maureen Lafond, Jean-François Arsenijevic, Yvan Kenna, Margaret A. Maguire, Casey A. Corey, David P. Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title | Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title_full | Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title_fullStr | Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title_full_unstemmed | Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title_short | Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate |
title_sort | gene transfer with aav9-php.b rescues hearing in a mouse model of usher syndrome 3a and transduces hair cells in a non-human primate |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6297893/ https://www.ncbi.nlm.nih.gov/pubmed/30581889 http://dx.doi.org/10.1016/j.omtm.2018.11.003 |
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