Lentiviral (LV) Gene Therapy for Adenosine Deaminase (ADA) Deficiency

Phase I/II, Historical Controlled, Open-label, Non-randomised, Single-centre Trial to Assess the Safety and Efficacy of EF1αS-ADA Lentiviral Vector Mediated Gene Modification of Autologous CD34+ Cells From ADA-deficient Individuals

This is a historically controlled, non-randomized Phase I/II clinical trial to assess the safety and efficacy of autologous transplantation of CD34+ hematopoietic stem/progenitor cells (HSPCs), obtained from infants affected by ADA-SCID, following transduction of the HSPCs with a lentiviral vector (LV) carrying the human ADA complementary DNA (cDNA) under the control of the elongation factor 1 alpha shortened (EFS) promoter. Subjects treated in the trial receive the infusion of autologous, transduced cells following marrow cytoreduction with busulfan. The outcomes are compared to those observed in a historical control group of patients who received an allogeneic hematopoietic stem cell transplant (HSCT).

This Phase I/II clinical trial will be performed at Great Ormond Street Hospital (GOSH), London, United Kingdom.

Gene Therapy (On Trial)

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing or by confirmed absence of <3% of ADA enzymatic activity in peripheral blood (or for neonates) in umbilical cord blood erythrocytes and/or leukocytes or in cultured fetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of Polyethylene glycol-modified ADA (PEG-ADA) replacement therapy
2. Patients who lack a fully Human leukocyte antigen (HLA)-matched family donor
3. Patients (male or female) <5 years of age OR Patients (male or female) ≥ 5 years to 15 years of age who have preserved thymic function as evidenced by presence of >10 % naïve T cells (CD4+45RA+27+ cells)
4. Parental/guardian signed informed consent

Exclusion Criteria:

1. Cytogenetic abnormalities on peripheral blood
2. Evidence of active malignant disease
3. Known sensitivity to busulfan
4. If applicable, confirmed pregnancy (to be tested in patients above 12 years old)

Gene Therapy (CUP)

A group of patients were treated under CUP (GOSH special license) either because the study was not yet open and patients needed urgent treatment, or because they were outside of the inclusion/exclusion criteria or received Investigational Medicinal Product (IMP) followed a different process (ie, received in two infusions). Patients followed the same protocol steps and study visits.

Historical Control Group

Inclusion Criteria:

1. Diagnosis of ADA-SCID confirmed by DNA sequencing OR by confirmed absence of <3% of ADA enzymatic activity in peripheral blood or (for neonates) in umbilical cord blood erythrocytes and/or leucocytes or in cultured foetal cells derived from either chorionic villus biopsy or amniocentesis, prior to institution of PEG-ADA replacement therapy
2. Patients (male or female) between 0-18 years at time of treatment
3. Patient treated with allogeneic haematopoietic stem cell transplantation since 2000