Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency

Adenosine-deaminase-deficient SCID was the first inherited disease to be treated with gene therapy. This life-threatening disorder is characterized by a purine defect that leads to impaired immune functions, recurrent infections and systemic metabolic abnormalities. The early gene therapy trials showed the safety and feasibility of engineering haematopoietic stem cells and peripheral blood lymphocytes using retroviral vectors. However, all patients were maintained on enzyme-replacement therapy, which prevented the evaluation of its efficacy and abolished the selective advantage for gene-corrected cells. It is only recently that the clinical efficacy of gene therapy has been investigated in the absence of enzyme-replacement therapy. Results of these studies showed that gene therapy with peripheral blood lymphocytes allowed correction of the T-cell defect, but provided insufficient systemic detoxification. Gene transfer in bone marrow stem cells, associated with non-myeloablative conditioning, allowed full immunological and metabolic correction of the adenosine-deaminase defect with clinical benefit. These results have important implications for future applications of gene therapy in other blood-borne disorders.