Lymphoid development and function in X-linked severe combined immunodeficiency mice after stem cell gene therapy

Mutations of the common gamma chain (gammac) of cytokine receptors cause X- linked severe combined immunodeficiency (XSCID), a candidate disease for ge ne therapy. Using an XSCID murine model, we have tested the feasibility of stem cell gene correction. XSCID bone marrow (BM) cells were transduced wit h a retroviral vector expressing the murine gammac (m gammac) and engrafted in irradiated XSCID animals. Transplanted mice developed mature B cells, n aive T cells, and mature natural killer (NK) cells, all of which were virtu ally absent in untreated mice. The m gammac transgene was detected in all t reated mice, and we could demonstrate m gammac expression in newly develope d lymphocytes at both the RNA and protein level. In addition, treated mice showed T cell proliferation responses to mitogens and production of antigen -specific antibodies upon immunization. Four of seven treated animals showe d a clear increase of the transgene positive cells, suggesting in vivo sele ctive advantage for gene-corrected cells. Altogether, these results show th at retroviral-mediated gene transfer can improve murine XSCID and suggest t hat similar strategies may prove beneficial in human clinical trials.