Severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) has been considered as one of the best candidate disease for clinical gene therapy. In deed, the first clinical gene therapy trial was performed in 1990-1991 for two patients with ADA-SCID using retrovirus vector (LASN) targeting peripheral T lymphocytes. However, it has taken more than 10 years to achieve a successful hematopoietic stem cell (HSC) gene therapy for patients with ADA-SCID. Recently, two different trials of HSC gene therapy for ADA-SCID were performed with the contrast outcome. The US trial, with concomitant PEG-ADA enzyme replacement for safety's sake, resulted in no apparent clinical improvement. In contrast, Italian group tried under the condition of absent PEG-ADA and mild pre-conditioning with great success. However, it is not known whether preconditioning would be essential to achieve a successful HSC gene therapy for ADA-SCID.
Here we present the results of our recent HSC gene therapy trial, in a different way from the above two trials in protocol, for two patients (4 year-old girl and 13 year-old boy) with ADA-SCID. PEG-ADA was discontinued approximately 4 weeks before treatment and the patients did not have any myelopreparative pre-conditioning. After the discontinuation of PEG-ADA, decreased number of peripheral lymphocytes, liver enzyme abnormalities and anorexia became evident in the patients, reflecting generalized accumulation of toxic metabolites of dAXP due to ADA-deficient status. Bone marrow CD34+ cells, prepared and transduced ex vivo with retroviral vector GCsapM-ADA, were infused to the patients. One week after the treatment, liver enzyme abnormalities and anorexia started to improve accompanied with decreasing blood dAXP levels, indicating continuous ADA-transgene expression in the patients. In both the patients, vector sequences were detected in peripheral blood nuclear cells and bone morrow progenitor cells. ADA enzyme activities in their lymphocytes were clearly increasing. Although their peripheral lymphocyte number is still low and IVIG replacement is needed, both the patients are doing well in normal school life without PEG-ADA more than one and half years. So far, no serious adverse events are observed. Careful follow-up including evaluation of their immunological status and monitoring vector insertional sites are on going.
S11. Gene and Cell Therapy for Relapsed Leukemia after