This is a phase I/II protocol to evaluate the safety and efficacy of ADA gene transfer into hematopoietic stem/progenitor cells for the treatment of adenosine deaminase (ADA)-deficiency. This condition is an autosomal recessive form of Severe Combined Immunodeficiency (SCID) characterized by impaired immune responses, recurrent infections, failure to thrive and systemic toxicity due to accumulation of purine metabolites. Transplants from an HLA-identical sibling donor is the treatment of choice, but available for a minority of patients. The use of alternative bone marrow donors or enzyme replacement therapy is associated with important drawbacks. The drug product studied in this protocol consists of autologous CD34+ hematopoietic stem/progenitor cells engineered ex vivo with a retroviral vector encoding the therapeutic gene ADA. The engineered CD34+ cells are infused following a nonmyeloablative conditioning with busulfan to make space in the bone marrow. The study objectives are: a) to evaluate the safety and the clinical efficacy of gene therapy, in the absence of enzyme replacement therapy; b) to evaluate the biological activity (engraftment, ADA expression) of ADA transduced CD34+ cells and their hematopoietic progeny. c) to evaluate the immunological reconstitution and purine metabolism after gene therapy.
Primary Outcome Measures:
- survival [ Time Frame: minimum of 1 year ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Change in the rate of severe infection [ Time Frame: During follow up ] [ Designated as safety issue: No ]
- T-lymphocyte counts [ Time Frame: one year ] [ Designated as safety issue: No ]
- Modification of the systemic metabolic defect [ Time Frame: one year ] [ Designated as safety issue: No ]
- presence of genetically modified cells in the BM and PB [ Time Frame: one year ] [ Designated as safety issue: No ]
Estimated Enrollment: |
10 |
Study Start Date: |
October 2002 |
CD34+ cells: Experimental
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Genetic: Gene transduced CD34+ cells
infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with Busulphan
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The safety of the study will be evaluated by description of all adverse events and adverse drug reactions.
The study is aimed at reaching the minimum sample size of ten patients.