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...

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Main Authors:	Denise A. Carbonaro-Sarracino, Krista Chun, Danielle N. Clark, Michael L. Kaufman, Xiangyang Jin, Xiaoyan Wang, Donald B. Kohn
Format:	Article
Language:	English
Published:	Elsevier 2021-03-01
Series:	Molecular Therapy: Methods & Clinical Development
Subjects:	AAV vector gene therapy lentiviral vector ADA-SCID ADA-deficiency inborn errors of metabolism
Online Access:	http://www.sciencedirect.com/science/article/pii/S232905012100022X

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spelling	doaj-6f56e2bbb6c145109472570c3a34f96d2021-03-13T04:23:55ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012021-03-0120765778Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCIDDenise A. Carbonaro-Sarracino0Krista Chun1Danielle N. Clark2Michael L. Kaufman3Xiangyang Jin4Xiaoyan Wang5Donald B. Kohn6Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Corresponding author: Denise A. Carbonaro-Sarracino, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 610 Charles E. Young Drive E, Los Angeles, CA 90095, USA.Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; The Eli & Edythe Broad Center for Stem Cells and Regenerative Medicine, University of California, Los Angeles, CA 90095, USAAdenosine 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.http://www.sciencedirect.com/science/article/pii/S232905012100022XAAV vectorgene therapylentiviral vectorADA-SCIDADA-deficiencyinborn errors of metabolism
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Denise A. Carbonaro-Sarracino Krista Chun Danielle N. Clark Michael L. Kaufman Xiangyang Jin Xiaoyan Wang Donald B. Kohn
spellingShingle	Denise A. Carbonaro-Sarracino Krista Chun Danielle N. Clark Michael L. Kaufman Xiangyang Jin Xiaoyan Wang Donald B. Kohn Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID Molecular Therapy: Methods & Clinical Development AAV vector gene therapy lentiviral vector ADA-SCID ADA-deficiency inborn errors of metabolism
author_facet	Denise A. Carbonaro-Sarracino Krista Chun Danielle N. Clark Michael L. Kaufman Xiangyang Jin Xiaoyan Wang Donald B. Kohn
author_sort	Denise A. Carbonaro-Sarracino
title	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_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_sort	gene delivery using aav8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ada-deficient scid
publisher	Elsevier
series	Molecular Therapy: Methods & Clinical Development
issn	2329-0501
publishDate	2021-03-01
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.
topic	AAV vector gene therapy lentiviral vector ADA-SCID ADA-deficiency inborn errors of metabolism
url	http://www.sciencedirect.com/science/article/pii/S232905012100022X
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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

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