New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and progress in gene therapy.

PURPOSE OF REVIEW: Adenosine deaminase (ADA)- deficient severe combined immunodeficiency (SCID) is a complex metabolic and immunological disorder, characterized by a severe immunodeficiency due to the accumulation of purine metabolites in plasma and cells. This review summarizes recent findings on the pathogenesis of immunological and nonimmunological defects in ADA deficiency and the successful outcome of gene therapy trials for this condition. RECENT FINDINGS: Recent reports show that ADA-SCID is associated with an increased frequency of autoimmune manifestations and high risk of central nervous system (CNS) complications even after bone marrow transplantation. It remains unclear to what extent infection-related or disease-specific factors correlate with this divergent outcome.Recent trials represented the first demonstration of long-term clinical efficacy of HSC gene therapy for ADA-SCID, underlining that gene therapy has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions. Molecular studies showed that the retroviral integration profile after successful gene therapy did not cause selection or expansion of malignant cell clones in vivo. SUMMARY: Gene therapy for ADA-deficient SCID is an effective treatment, providing long-term clinical benefit for affected patients. Future research will be needed to address the occurrence of autoimmune manifestations and nonimmunological defects in order to improve patients' long-term prospects.