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Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice
Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group US
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941048/ https://www.ncbi.nlm.nih.gov/pubmed/36797483 http://dx.doi.org/10.1038/s41591-022-02190-7 |
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author | Reichart, Daniel Newby, Gregory A. Wakimoto, Hiroko Lun, Mingyue Gorham, Joshua M. Curran, Justin J. Raguram, Aditya DeLaughter, Daniel M. Conner, David A. Marsiglia, Júlia D. C. Kohli, Sajeev Chmatal, Lukas Page, David C. Zabaleta, Nerea Vandenberghe, Luk Liu, David R. Seidman, Jonathan G. Seidman, Christine |
author_facet | Reichart, Daniel Newby, Gregory A. Wakimoto, Hiroko Lun, Mingyue Gorham, Joshua M. Curran, Justin J. Raguram, Aditya DeLaughter, Daniel M. Conner, David A. Marsiglia, Júlia D. C. Kohli, Sajeev Chmatal, Lukas Page, David C. Zabaleta, Nerea Vandenberghe, Luk Liu, David R. Seidman, Jonathan G. Seidman, Christine |
author_sort | Reichart, Daniel |
collection | PubMed |
description | Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9—to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM. |
format | Online Article Text |
id | pubmed-9941048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-99410482023-02-22 Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice Reichart, Daniel Newby, Gregory A. Wakimoto, Hiroko Lun, Mingyue Gorham, Joshua M. Curran, Justin J. Raguram, Aditya DeLaughter, Daniel M. Conner, David A. Marsiglia, Júlia D. C. Kohli, Sajeev Chmatal, Lukas Page, David C. Zabaleta, Nerea Vandenberghe, Luk Liu, David R. Seidman, Jonathan G. Seidman, Christine Nat Med Article Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies—an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9—to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM. Nature Publishing Group US 2023-02-16 2023 /pmc/articles/PMC9941048/ /pubmed/36797483 http://dx.doi.org/10.1038/s41591-022-02190-7 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Reichart, Daniel Newby, Gregory A. Wakimoto, Hiroko Lun, Mingyue Gorham, Joshua M. Curran, Justin J. Raguram, Aditya DeLaughter, Daniel M. Conner, David A. Marsiglia, Júlia D. C. Kohli, Sajeev Chmatal, Lukas Page, David C. Zabaleta, Nerea Vandenberghe, Luk Liu, David R. Seidman, Jonathan G. Seidman, Christine Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title | Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title_full | Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title_fullStr | Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title_full_unstemmed | Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title_short | Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
title_sort | efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9941048/ https://www.ncbi.nlm.nih.gov/pubmed/36797483 http://dx.doi.org/10.1038/s41591-022-02190-7 |
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