Work

1088. Stem Cell Gene Therapy with No Pre-Conditioning for the ADA-Deficiency Patients Leads to Generalized Detoxification and Delayed, but Steady Hematological Reconstitution

Year: 2006

Type: article

Abstract: In the previous meeting, we reported the initial follow-up of the two patients with adenosine deaminase (ADA)-deficiency whom we had treated in a clinical trial of retroviral-mediated stem cell gene therapy (SCGT). Our protocol is unique in that patients do not receive any kinds of marrow-preparative conditioning prior to infusion of gene-corrected autologous bone marrow (BM) cells. Since the successful cases of ADA gene therapy reported from Italy used low-dose busulfan to enhance the engraftment of gene-transduced BM cells, it is intriguing to see how the lack of conditioning affects the hematological and immunological reconstitution in our patients. Two patients (pt 1, a 4 year-old girl; pt 2, a 13 year-old boy) were given i.v. BM CD34+ cells transduced with the retroviral vector GCsapM-ADA following the cessation of ADA-enzyme (PEG- ADA) replacement. The first evidence of clinical benefits emerged in a form of systemic detoxification as we previously reported. Steady decrease of toxic metabolites, once accumulated shortly after PEG-ADA discontinuation, is still ongoing at present, 2 years after SCGT. Slow, but gradual increase of lymphocyte counts has followed as the second, reaching the recent values that rather surpass the pre- GT levels. T cells have been the most abundant population among the emerging lymphocytes in both patients, exhibiting relatively rapid development. Most striking is the appearance of peripheral B cells in pt 1 after long latency; B cells had never appeared during the first year, but then emerged and has shown a steady increase thereafter. NK cells showed similar reconstitution kinetics, with the evidence of 100% positive for the presence of ADA-transgene. Consistent with these observations, the proviral copy numbers in peripheral blood lymphocytes (PBL) of pt 1 have now reached 0.7 copies/cell and the latest value of ADA enzyme activity in PBL was shown to be near normal. Although pt 2 has shown much slower kinetics of lymphocyte development, he maintains healthy status with the recent evidence of improvement in T cell function. No serious adverse events, including clonal expansion of certain cell types, have been observed. Although some prophylactic measures are still necessary, both patients have been completely off PEG-ADA for longer than 2 years and now are ready for their new lives; pt 1 entering an elementary school and pt 2 proceeding to a high school. These results suggest that SCGT for ADA-deficiency without pre-conditioning can lead to meaningful hematological reconstitution and be a safe and effective treatment option for the patient who needs SCGT, especially when the conditioning may not be tolerated.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.1190