Update On The Safety And Efficacy Of Retroviral Gene Therapy For Immunodeficiency Due To Adenosine Deaminase Deficiency
Date
2016Author
Cicalese, Maria Pia
Ferrua, Francesca
Castagnaro, Laura
Pajno, Roberta
Barzaghi, Federica
Giannelli, Stefania
Dionisio, Francesca
Brigida, Immacolata
Bonopane, Marco
Casiraghi, Miriam
Tabucchi, Antonella
Carlucci, Filippo
Grunebaum, Eyal
Adeli, Mehdi
Bredius, Robbert G.
Puck, Jennifer M.
Stepensky, Polina
Tezcan, Ilhan
Rolfe, Katie
De Boever, Erika
Reinhardt, Rickey R.
Appleby, Jonathan
Ciceri, Fabio
Roncarolo, Maria Grazia
Aiuti, Alessandro
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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 from an HLA-matched sibling donor, although <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 1 cells transduced with a retroviral vector encoding the human ADA complementary DNA 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 inmultiple 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 were registered at www.clinicaltrials.gov as #NCT00598481.