Gene therapy for adenosine deaminase deficiency

Purpose of review Gene therapy for severe combined immunodeficiency due to adenosine deaminase deficiency has moved from the early trials of safety and feasibility to recent studies demonstrating efficacy and clinical benefit. This review describes the latest advances in gene therapy trials for this condition using peripheral blood lymphocytes or hematopoietic progenitors. Recent findings In the first patients with severe combined immunodeficiency due to adenosine deaminase deficiency treated with peripheral blood lymphocytes, transduced T cells have been shown to persist for over 10 years, expressing transgenic adenosine deaminase, but the therapeutic effect of gene therapy remained difficult to assess because of the concomitant treatment with bovine adenosine deaminase conjugated to polyethylene-glycol (PEG-ADA). A recent report showed that discontinuation of PEG-ADA resulted in a strong selective advantage of gene corrected T cells associated with restoration of T cell functions and antibody responses to neoantigen, but incomplete correction of the metabolic defect. Follow-up studies in patients treated with engineered hematopoietic progenitors in the early trials revealed low marking levels of long-term living progenitors and limited clinical effect. Recently, an improved gene transfer protocol in bone marrow CD34(+) cells combined with low-dose busulfan resulted in multilineage, stable engraftment of transduced progenitors at substantial levels, restoration of immune functions, correction of the adenosine deaminase metabolic defect, and proven clinical benefit, in the absence of PEG-ADA. Overall, no adverse effect or toxicity has been observed in patients treated with adenosine deaminase gene transfer in mature lymphocytes or hematopoietic progenitors. Summary Gene transfer in hematopoietic stem cells combined with nonmyeloablative conditioning is efficacious and might be extended to the treatment of other inherited and acquired disorders of the hematopoietic system.