Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency

Maria Pia Cicalese, Francesca Ferrua, Laura Castagnaro, Roberta Pajno, Federica Barzaghi, Stefania Giannelli, Francesca Dionisio, Immacolata Brigida, Marco Bonopane, Miriam Casiraghi, Antonella Tabucchi, Filippo Carlucci, Eyal Grunebaum, Mehdi Adeli, Robbert G. Bredius, Jennifer M. Puck, Polina Stepensky, Ilhan Tezcan, Katie Rolfe, Erika De Boever, Rickey R. Reinhardt, Jonathan Appleby, Fabio Ciceri, Maria Grazia Roncarolo and Alessandro Aiuti

Key points

  • 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 as #NCT00598481.

  • Submitted January 4, 2016.
  • Accepted April 14, 2016.