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CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice
Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) ve...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803634/ https://www.ncbi.nlm.nih.gov/pubmed/33473359 http://dx.doi.org/10.1016/j.omtm.2020.11.014 |
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author | Stone, Daniel Long, Kelly R. Loprieno, Michelle A. De Silva Feelixge, Harshana S. Kenkel, Elizabeth J. Liley, R. Matt Rapp, Stephen Roychoudhury, Pavitra Nguyen, Thuy Stensland, Laurence Colón-Thillet, Rossana Klouser, Lindsay M. Weber, Nicholas D. Le, Connie Wagoner, Jessica Goecker, Erin A. Li, Alvason Zhenhua Eichholz, Karsten Corey, Lawrence Tyrrell, D. Lorne Greninger, Alexander L. Huang, Meei-Li Polyak, Stephen J. Aubert, Martine Sagartz, John E. Jerome, Keith R. |
author_facet | Stone, Daniel Long, Kelly R. Loprieno, Michelle A. De Silva Feelixge, Harshana S. Kenkel, Elizabeth J. Liley, R. Matt Rapp, Stephen Roychoudhury, Pavitra Nguyen, Thuy Stensland, Laurence Colón-Thillet, Rossana Klouser, Lindsay M. Weber, Nicholas D. Le, Connie Wagoner, Jessica Goecker, Erin A. Li, Alvason Zhenhua Eichholz, Karsten Corey, Lawrence Tyrrell, D. Lorne Greninger, Alexander L. Huang, Meei-Li Polyak, Stephen J. Aubert, Martine Sagartz, John E. Jerome, Keith R. |
author_sort | Stone, Daniel |
collection | PubMed |
description | Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR-Staphylococcus aureus (Sa)Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir. Gene editing was detected in livers of five of eight HBV-specific AAV-SaCas9-treated mice, but not control mice, and mice with detectable HBV gene editing showed higher levels of SaCas9 delivery to HBV(+) human hepatocytes than those without gene editing. HBV-specific AAV-SaCas9 therapy significantly improved survival of human hepatocytes, showed a trend toward decreasing total liver HBV DNA and cccDNA, and was well tolerated. This work provides evidence for the feasibility and safety of in vivo gene editing for chronic HBV infections, and it suggests that with further optimization, this approach may offer a plausible way to treat or even cure chronic HBV infections. |
format | Online Article Text |
id | pubmed-7803634 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-78036342021-01-19 CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice Stone, Daniel Long, Kelly R. Loprieno, Michelle A. De Silva Feelixge, Harshana S. Kenkel, Elizabeth J. Liley, R. Matt Rapp, Stephen Roychoudhury, Pavitra Nguyen, Thuy Stensland, Laurence Colón-Thillet, Rossana Klouser, Lindsay M. Weber, Nicholas D. Le, Connie Wagoner, Jessica Goecker, Erin A. Li, Alvason Zhenhua Eichholz, Karsten Corey, Lawrence Tyrrell, D. Lorne Greninger, Alexander L. Huang, Meei-Li Polyak, Stephen J. Aubert, Martine Sagartz, John E. Jerome, Keith R. Mol Ther Methods Clin Dev Original Article Chronic hepatitis B virus (HBV) infection is a major public health problem. New treatment approaches are needed because current treatments do not target covalently closed circular DNA (cccDNA), the template for HBV replication, and rarely clear the virus. We harnessed adeno-associated virus (AAV) vectors and CRISPR-Staphylococcus aureus (Sa)Cas9 to edit the HBV genome in liver-humanized FRG mice chronically infected with HBV and receiving entecavir. Gene editing was detected in livers of five of eight HBV-specific AAV-SaCas9-treated mice, but not control mice, and mice with detectable HBV gene editing showed higher levels of SaCas9 delivery to HBV(+) human hepatocytes than those without gene editing. HBV-specific AAV-SaCas9 therapy significantly improved survival of human hepatocytes, showed a trend toward decreasing total liver HBV DNA and cccDNA, and was well tolerated. This work provides evidence for the feasibility and safety of in vivo gene editing for chronic HBV infections, and it suggests that with further optimization, this approach may offer a plausible way to treat or even cure chronic HBV infections. American Society of Gene & Cell Therapy 2020-11-26 /pmc/articles/PMC7803634/ /pubmed/33473359 http://dx.doi.org/10.1016/j.omtm.2020.11.014 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 Stone, Daniel Long, Kelly R. Loprieno, Michelle A. De Silva Feelixge, Harshana S. Kenkel, Elizabeth J. Liley, R. Matt Rapp, Stephen Roychoudhury, Pavitra Nguyen, Thuy Stensland, Laurence Colón-Thillet, Rossana Klouser, Lindsay M. Weber, Nicholas D. Le, Connie Wagoner, Jessica Goecker, Erin A. Li, Alvason Zhenhua Eichholz, Karsten Corey, Lawrence Tyrrell, D. Lorne Greninger, Alexander L. Huang, Meei-Li Polyak, Stephen J. Aubert, Martine Sagartz, John E. Jerome, Keith R. CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title | CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title_full | CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title_fullStr | CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title_full_unstemmed | CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title_short | CRISPR-Cas9 gene editing of hepatitis B virus in chronically infected humanized mice |
title_sort | crispr-cas9 gene editing of hepatitis b virus in chronically infected humanized mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803634/ https://www.ncbi.nlm.nih.gov/pubmed/33473359 http://dx.doi.org/10.1016/j.omtm.2020.11.014 |
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