The proposed study population is affected with adenosine deaminase-deficient severe combined immune deficiency (ADA-SCID), an autosomal recessive congenital immune deficiency. The basis of the proposed study (and product) is retroviral-mediated transduction of autologous, bone marrow derived CD34 hematopoietic progenitor cells with the MND-ADA retroviral vector in a 5-day cell processing period. Transduction is followed by infusion of the washed cells into subjects not receiving enzyme replacement therapy with polyethylene-conjugated ADA who have had their PEG-ADA injections discontinued, and have undergone bone marrow cytoreductive therapy with a single non-ablative treatment course of busulfan. The dose of cells infused will be determined by the patient-to-patient variation of the number of progenitors available from individual patients. Statistical analyses post-infusion will help determine the dose-response of the number of cells infused to the level of engraftment and resulting level of immune reconstitution. Following cellular infusion, a primary clinical end-point will be the absolute numbers of T and B lymphocytes containing the transduced ADA gene by Taqman PCR analyses. Based on the degree of marking of lymphocytes and of granulocytes, the selective advantage of lymphocytes may be gauged. Subjects will be monitored for the development of clonal proliferation, under the 15-year plan required by the FDA. One major aim of the study will be to see if subjects can remain off PEG-ADA and maintain protective immunity from the population of transduced lymphocytes arising from transduced progenitors. If sufficient gene-modified cells result, and PEG-ADA enzyme replacement therapy can be permanently discontinued, the advantage of this therapeutic approach may change the standard of care for these patients.
