Survival was 100% for 18 patients with ADA-SCID treated with genetically modified CD34+ cells (2.3-13.4 years follow up, median 6.9 years).
Long-term engraftment, immune reconstitution, and fewer severe infections in 15/18 patients were observed without leukemic transformation.
Adenosine deaminase (ADA) deficiency is a rare, autosomal recessive systemic metabolic disease characterized by severe combined immunodeficiency (SCID). The treatment of choice for ADA-deficient SCID (ADA-SCID) is hematopoietic stem cell transplant (SCT) from a human leukocyte antigen (HLA)-matched sibling donor, although fewer than 25% of patients have such a donor available. Enzyme replacement therapy (ERT) partially and temporarily relieves immunodeficiency. We investigated the medium-term outcome of gene therapy (GT) in 18 patients with ADA-SCID for whom an HLA-identical family donor was not available; most were not responding well to ERT. Patients were treated with an autologous CD34+ enriched cell fraction that contained CD34+ cells transduced with a retroviral vector encoding the human ADA cDNA sequence (GSK2696273) as part of single-arm, open-label studies or compassionate use programs. Overall survival was 100% over 2.3 to 13.4 years (median: 6.9 years). Gene-modified cells were stably present in multiple lineages throughout follow up. GT resulted in a sustained reduction in the severe infection rate from 1.17 events per person-year to 0.17 events per person-year (n=17, Patient 1 data not available). Immune reconstitution was demonstrated by normalization of T cell subsets (CD3+, CD4+, and CD8+), evidence of thymopoiesis, and sustained T cell proliferative capacity. B cell function was evidenced by immunoglobulin production, decreased intravenous immunoglobulin use, and antibody response after vaccination. All 18 patients reported infections as adverse events; infections of respiratory and gastrointestinal tracts were reported most frequently. No events indicative of leukemic transformation were reported. Trial details are registered at www.clinicaltrials.gov as #NCT00598481.
- Submitted January 4, 2016.
- Accepted April 14, 2016.
- Copyright © 2016 American Society of Hematology