X-linked Severe Combined Immunodeficiency (X-SCID) is a life-threatening disease that affects young children who are born without a functioning immune system. As a result, they will die from overwhelming infections in the few years of life if not treated quickly with some form of therapy that fully restores their immune system. Bone marrow transplant has been used for this purpose, but is only maximally effective in half of the cases where a matched brother or sister can serve as a bone marrow donor. For the other patients, various experimental therapies have been tested including gene therapy, where a normal copy of the X-SCID gene is inserted into the patient’s own bone marrow stem cells. Early results with gene therapy have resulted in a high incidence of leukemia due to the procedure. Later gene therapy trials appear safer but only correct a subset of the immune defects that cause X-SCID. In particular, gene therapy has not been successful in restoring antibody production in the patients, so that they remain dependent of regular and expensive injections of human antibodies for the remainder of their life. In this CIRM-sponsored gene therapy trial, we have tested a new method for performing gene therapy in X-SCID infants that uses for the first time a chemotherapy drug called busulfan to increase the number of corrected bone marrow cells after gene therapy. The busulfan is given at a low dose and is monitored in every patient to achieve tight control of dosing and to avoid toxicity. The other unique aspect is that we use a lentiviral vector to transfer the normal copy of the X-SCID gene to the patient. The lentiviral vector is both safer in terms of not causing leukemia and is more efficient at transferring the therapeutic gene. To date, we have treated 7 patients with this technique and have noted robust immune correction in all cases, including correction of antibody production allowing us to stop antibody replacement therapy in 3 cases to date. Other immune functions have also normalized, these children have cleared pre-existing viral and bacterial infections, and have been taken off protective isolation. To date, this new form of gene therapy for X-SCID appears to be both safe and effective, if not fully curative, although more time will be necessary to fully evaluate this treatment. We believe this new approach provides the best way to treat X-SCID children that lack a matched sibling donor for stem cell transplant.