Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency
2016
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 fractionthat contained CD34 + cells transduced with a retroviral vector encoding the human
ADAcDNA 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.
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