Stem cell gene therapy for genetic diseases
Stem cell gene therapy represents the best or the only therapeutic option for a munber of genetic diseases. For disorders of the lympho-hematopoietic system, bone marrow (BM) transplantation is associated with elevated morbidity and mortality if an HLA-identical sibling donor is not available. Gene therapy with hematopoietic stem cells (HSC) may represent a definitive treatment for SCID patients. We have treated six ADA-deficient children (age: 7-30 months) who lacked an HLA-identical donor. Autologous BM CD34+ cells were transduced with a retroviral vector encoding ADA and reinfused in the patients (range 0.9-8.6x106/Kg) following a nonmyeloablative conditioning with busulfan (2 mg/Kg/day). Following gene therapy, vector-ADA+ cells became progressively the large majority of T, B and NK cells. This resulted in the progressive increase of peripheral blood lymphocyte counts, restoration of thymopoiesis, and normalization of proliferative responses to mitogens and antigens. Serum Ig levels improved, and production of specific antibodies after antigen vaccination was observed in Pt1 and Pt3, following IVIG discontinuation. Sustained multilineage engraftment of gene corrected HSC was achieved in the BM and peripheral blood, at higher levels in Pt1 and Pt3 (5-10%). Overall, the level of immune reconstitution and myeloid engraftment correlated both with the dose of infused transduced CD34+ cells and the actual degree of myelosuppression. Sustained ADA expression in different cells led to a dramatic decrease in RBC dAXP metabolites and amelioration of systemic toxicity. All the children are presently at home, healthy and they did not experience any severe infections. There was no evidence of clonal expansion or adverse effect after gene therapy in a follow up extending to over 5 years. In conclusion, considering the current limitations of other therapeutic approaches, gene therapy should be extended to other ADA-SCID patients in demand of an efficacious treatment.