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Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID
Adenosine deaminase (ADA) deficiency is an inborn error of metabolism affecting multiple systems and causing severe combined immunodeficiency. We tested intravenous administration of recombinant adeno-associated virus (AAV) 2/8-ADA vector in ADA-deficient neonate and adult mice or as part of a bimod...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940710/ https://www.ncbi.nlm.nih.gov/pubmed/33738330 http://dx.doi.org/10.1016/j.omtm.2021.02.007 |
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author | Carbonaro-Sarracino, Denise A. Chun, Krista Clark, Danielle N. Kaufman, Michael L. Jin, Xiangyang Wang, Xiaoyan Kohn, Donald B. |
author_facet | Carbonaro-Sarracino, Denise A. Chun, Krista Clark, Danielle N. Kaufman, Michael L. Jin, Xiangyang Wang, Xiaoyan Kohn, Donald B. |
author_sort | Carbonaro-Sarracino, Denise A. |
collection | PubMed |
description | Adenosine deaminase (ADA) deficiency is an inborn error of metabolism affecting multiple systems and causing severe combined immunodeficiency. We tested intravenous administration of recombinant adeno-associated virus (AAV) 2/8-ADA vector in ADA-deficient neonate and adult mice or as part of a bimodal approach comprised of rAAV treatment at birth followed by infusion of lentiviral vector (LV)-modified lineage-depleted bone marrow cells at 8 weeks. ADA(−/−) mice treated with rAAV and enzyme replacement therapy (ERT) for 30 days were rescued from the lethal pulmonary insufficiency, surviving out to 180 days without further treatment. rAAV vector copy number (VCN) was highest in liver, lung, and heart and was associated with near-normal ADA activity and thymocyte development. In the bimodal approach, rAAV-mediated ADA expression supported survival during the 4 weeks before infusion of the LV-modified bone marrow cells and during the engraftment period. Conditioning prior to infusion may have resulted in the replacement of rAAV marked cells in marrow and liver, with LV VCN 100- to 1,000-fold higher in hematopoietic tissue compared with rAAV VCN, and was associated with immune cell reconstitution. In conclusion, a bimodal approach may be an alternative for patients without reliable access to ERT before receiving a stem cell transplant or gene therapy. |
format | Online Article Text |
id | pubmed-7940710 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-79407102021-03-17 Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID Carbonaro-Sarracino, Denise A. Chun, Krista Clark, Danielle N. Kaufman, Michael L. Jin, Xiangyang Wang, Xiaoyan Kohn, Donald B. Mol Ther Methods Clin Dev Original Article Adenosine deaminase (ADA) deficiency is an inborn error of metabolism affecting multiple systems and causing severe combined immunodeficiency. We tested intravenous administration of recombinant adeno-associated virus (AAV) 2/8-ADA vector in ADA-deficient neonate and adult mice or as part of a bimodal approach comprised of rAAV treatment at birth followed by infusion of lentiviral vector (LV)-modified lineage-depleted bone marrow cells at 8 weeks. ADA(−/−) mice treated with rAAV and enzyme replacement therapy (ERT) for 30 days were rescued from the lethal pulmonary insufficiency, surviving out to 180 days without further treatment. rAAV vector copy number (VCN) was highest in liver, lung, and heart and was associated with near-normal ADA activity and thymocyte development. In the bimodal approach, rAAV-mediated ADA expression supported survival during the 4 weeks before infusion of the LV-modified bone marrow cells and during the engraftment period. Conditioning prior to infusion may have resulted in the replacement of rAAV marked cells in marrow and liver, with LV VCN 100- to 1,000-fold higher in hematopoietic tissue compared with rAAV VCN, and was associated with immune cell reconstitution. In conclusion, a bimodal approach may be an alternative for patients without reliable access to ERT before receiving a stem cell transplant or gene therapy. American Society of Gene & Cell Therapy 2021-02-15 /pmc/articles/PMC7940710/ /pubmed/33738330 http://dx.doi.org/10.1016/j.omtm.2021.02.007 Text en © 2021 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Carbonaro-Sarracino, Denise A. Chun, Krista Clark, Danielle N. Kaufman, Michael L. Jin, Xiangyang Wang, Xiaoyan Kohn, Donald B. Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title | Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title_full | Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title_fullStr | Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title_full_unstemmed | Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title_short | Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID |
title_sort | gene delivery using aav8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ada-deficient scid |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940710/ https://www.ncbi.nlm.nih.gov/pubmed/33738330 http://dx.doi.org/10.1016/j.omtm.2021.02.007 |
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