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

Denise A Carbonaro-Sarracino, Krista Chun + Show 5 more

Open Access

https://doi.org/10.1016/j.omtm.2021.02.007

Copy DOI

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.

Highlights

Adenosine deaminase (ADA) deficiency is an inborn error of metabolism caused by a mutation in the ADA gene and results in a severe combined immunodeficiency (ADA-SCID) and other system manifestations.[1,2] ADA is a critical enzyme in the purine salvage pathway and is responsible for catalyzing the deamination of metabolites, deoxyadenosine and adenosine, to deoxyinosine and inosine, respectively.[2]
ADA deficiency is an inborn error of metabolism that causes SCID, as well as other system disorders, including pulmonary insufficiency, hepatic and renal dysfunction, skeletal abnormalities, and neurological manifestations, such as hearing loss, behavioral issues, and in some cases, cognitive deficits.[5]
Patients with ADA-deficient SCID are often diagnosed in infancy, and without treatment patients would die within the first years of life

Summary

Introduction

Adenosine deaminase (ADA) deficiency is an inborn error of metabolism caused by a mutation in the ADA gene and results in a severe combined immunodeficiency (ADA-SCID) and other system manifestations.[1,2] ADA is a critical enzyme in the purine salvage pathway and is responsible for catalyzing the deamination of metabolites, deoxyadenosine and adenosine, to deoxyinosine and inosine, respectively.[2].

Methods

Results

Conclusion