Correction of ADA-SCID by Stem Cell Gene Therapy Combined with Nonmyeloablative Conditioning

TLDR

Hematopoietic stem cell gene therapy for ADA‑deficient SCID has limited efficacy due to a low proportion of engrafted corrected HSCs. The study aims to improve gene transfer into HSCs using nonmyeloablative conditioning. The protocol was applied to two patients lacking enzyme replacement therapy, enabling assessment of gene therapy alone. Sustained engraftment of engineered HSCs produced increased lymphocyte counts, enhanced immune responses, reduced toxic metabolites, and both patients remain clinically well, confirming the safety and efficacy of this approach for SCID.

Abstract

Hematopoietic stem cell (HSC) gene therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) has shown limited clinical efficacy because of the small proportion of engrafted genetically corrected HSCs. We describe an improved protocol for gene transfer into HSCs associated with nonmyeloablative conditioning. This protocol was used in two patients for whom enzyme replacement therapy was not available, which allowed the effect of gene therapy alone to be evaluated. Sustained engraftment of engineered HSCs with differentiation into multiple lineages resulted in increased lymphocyte counts, improved immune functions (including antigen-specific responses), and lower toxic metabolites. Both patients are currently at home and clinically well, with normal growth and development. These results indicate the safety and efficacy of HSC gene therapy combined with nonmyeloablative conditioning for the treatment of SCID.