Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID

Denise A Carbonaro-Sarracino; Krista Chun; Danielle N Clark; Michael L Kaufman; Xiangyang Jin; Xiaoyan Wang; Donald B Kohn

doi:10.1016/j.omtm.2021.02.007

Gene delivery using AAV8 in vivo for disease stabilization in a bimodal gene therapy approach for the treatment of ADA-deficient SCID

Mol Ther Methods Clin Dev. 2021 Feb 15:20:765-778. doi: 10.1016/j.omtm.2021.02.007. eCollection 2021 Mar 12.

Authors

Denise A Carbonaro-Sarracino¹, Krista Chun¹, Danielle N Clark¹, Michael L Kaufman¹, Xiangyang Jin¹, Xiaoyan Wang², Donald B Kohn^{1

3

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Affiliations

¹ Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of General Internal Medicine and Health Services Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ The Eli & Edythe Broad Center for Stem Cells and Regenerative Medicine, University of California, Los Angeles, CA 90095, USA.

Abstract

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.

Keywords: AAV vector; ADA-SCID; ADA-deficiency; gene therapy; hematopoietic stem cells; inborn errors of metabolism; lentiviral vector; severe combined immunodeficiency.

Abstract

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