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

Phase 2

Completed

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Gene Therapy	Gene Therapy	Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan
Gene Therapy	Busulfan	Infusion of autologous CD34+ cells transduced with retroviral vector encoding ADA after non-myeloablative conditioning with busulfan

Primary Outcome Measures

Name	Time	Method
Survival	baseline to 3 years post gene therapy	From post-treatment to up to 3 years

Secondary Outcome Measures

Name	Time	Method
CD3+ Cell Counts	baseline up to 3 years post gene therapy	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).
Rate of Severe Infections	Before Treatment and 3-months post-treatment up to 3 years	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.