ADA Gene Transfer Into Hematopoietic Stem/Progenitor Cells for the Treatment of ADA-SCID (Gene-ADA)

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 human leukocyte-antigen (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 cluster of differentiation (CD)34+ 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.

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.

Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan

Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan

Severe infections were defined as those that required hospitalization or those that prolonged hospitalization. The rate of infection was estimated as number of severe infections over person-years of observation (free from severe infections) before and after treatment administration. The first 3 months after gene therapy were not considered in the post-gene therapy analysis, because all subjects were hospitalized during this period.

T-lymphocyte counts (CD3+): mean T-lymphocyte at Baseline and 3 years post gene therapy. Samples were taken from peripheral venous whole blood and tested by cytofluorometry; values are means (10^6/L).

Inclusion Criteria: ADA-SCID with no HLA-identical sibling donor available pediatric age and at least one of the following criteria: inadequate immune response after PEG-ADA for > 6 months patients who discontinued PEG-ADA due to intolerance, allergy or auto-immunity patients for whom enzyme replacement therapy is not a life long therapeutic option Exclusion Criteria: HIV infection history or current malignancy Patients who received a previous gene therapy treatment in the 12 months prior to receiving Strimvelis any other conditions dangerous for the patients according to the investigator

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