BONE-MARROW GENE-TRANSFER IN 3 PATIENTS WITH ADENOSINE-DEAMINASE DEFICIENCY

Adenosine deaminase (ADA) deficiency results in severe combined immune deficiency disease (SCID), which is fatal without treatment. Allogeni c bone marrow transplantation (BMT) is the treatment of choice if an H LA-identical sibling bone marrow donor is available, resulting in almo st 100% cure rate. BMT-related mortality is high patients lacking such a donor. For these patients, efficient transfer of a recombinant ADA gene into hematopoietic stem cells is a therapeutic option if it resul ts in the outgrowth of a 'genetically repaired' lymphoid system. Based on successful gene transfer studies in monkeys, we performed retrovir us-mediated gene transfer into CD34(+) bone marrow cells of three pati ents with ADA deficiency. Two patients received bovine ADA conjugated to polyethylene glycol (PEG-ADA); in the third patient, PEG-ADA was st arted 4 months after gene transfer. Gene transfer resulted in a 5-12% transduction frequency of in vitro colony forming cells (CFU-Cs). No t oxicity was observed during and after infusion of the graft. Following infusion of the transduced CD34(+) cells, transduced granulocytes and mononuclear cells persisted in the circulation for 3 months. In addit ion, the gene was present in the marrow of one of the patients at 6 mo nths after gene transfer. Expression of the gene was not detected. Aft er this period, the gene could not be detected. In monkey studies we s howed that myeloablation, which was not performed in the patients, may enhance engraftment of genetically modified cells. We hypothesize tha t lack of myeloablation, administration of bovine ADA and low numbers of transduced progenitor cells all may have contributed to the relativ e low numbers of transduced cells in the patients. Under these conditi ons, no selective advantage of the genetically corrected progenitor ce lls was observed.