Success and risk: Gene therapy for severe combined immunodeficiency

Abstract

SCIDs are a group of inherited disorders characterized by profound defects in both cellmediated and humoral immunity (Figure 1). These diseases represent the most severe forms of primary immunodeficiencies, affecting approximately 1 child in every 75000 livebirths. The molecular pathology of these disorders has been deter mined for the majority of cases (Table 1), which typi cally present in the first few months of life with failure to thrive, chronic diarrhoea and recurrent infections. Conventional treatment for SCID is HSCT (haemo poietic stem cell transplantation) with high longterm survival rates for transplants from genotypically matched family donors. For the majority of patients for whom a matched family donor is unavailable, how ever, mismatched procedures offer a poorer prognosis and may be associated with incomplete recovery of immunity. Gene therapy therefore presents an attractive therapeutic alternative, and several features of SCIDs make these disorders particularly amenable to correc tion by this technology. First, as stated above, the molecular basis of the majority of SCID phenotypes has been defined and at tributed to defects in single genes (Table 1). Secondly, treatment by HSCT is curative, supporting the notion that correction of a patient's own bone marrow stem cells will lead to restoration of immunity. The target stem cells are easily accessible (allowing gene therapy to be performed ex vivo) and, furthermore, correction of the gene defect in these cells should confer a strong growth and survival advantage in the SCID setting. The gene therapy procedure can therefore be performed without or with minimal chemotherapeutic conditioning. This concept is supported by the partial immunological re constitution observed in two patients following spon taneous mutationreversion events and demonstrates that the correction of even a small number of lymphoid precursors may confer significant therapeutic benefit1,2.