Originally published by 2 Minute Medicine® (view original article). Reused on AccessMedicine with permission.

1. Treatment with autologous CD34+ hematopoietic stem and progenitor cells transduced with human ADA via a lentiviral vector showed sustained ADA expression in patients with severe combined immunodeficiency from adenosine deaminase deficiency.

2. The lentiviral treatment showed persistent engraftment and nearly all patients discontinued immunoglobulin-replacement therapy.

Evidence Rating Level: 2 (Good)

Study Rundown:

Severe combined immunodeficiency due to adenose deaminase (ADA-SCID) is a disease of inborn errors of metabolism resulting in severely impaired immune function. Current treatments include enzyme-replacement therapy which does not fully repair the immune system or hematopoietic stem-cell transplant which carries infection or graft-vs-host disease risk. This study evaluated the efficacy and safety of autologous lentivirus-mediated transduction of ADA into CD34+ hematopoietic and progenitor cells as a treatment for immunodeficiency. The study determined a high event-free survival defined as the absence of enzyme-replacement therapy or rescue transplant. The study reported 90% of patients stopped receiving immunoglobulin-replacement therapy at 24 months in the United States cohort, while in the United Kingdom cohort, all patients no longer needed immunoglobulin therapy at 36 months. The main limitation of this study was the single-arm nature and lack of a comparator to the standard of care. Nonetheless, the study’s results are significant showing autologous stem-cell transplant has a comparable effect to the standard of care therapies without the need for continued immunosuppression.

In-Depth [prospective cohort]:

This was a single-arm, multi-center, of three prospective cohorts from the United States and the United Kingdom. Across the three cohorts, 50 patients were enrolled in the study. Children diagnosed with ADA-SCID and at least one month of age or older were included in the United States study. Children diagnosed with ADA-SCID and either younger than five years of age or between the ages of five and 15 with preserved thymic function were included in the United Kingdom study. For all three cohorts, children with an HLA-matched sibling were excluded from the studies. All patients were treated with autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) which were transduced with the human ADA gene via a self-inactivating lentiviral vector. The primary efficacy endpoints were overall survival and event-free survival at 12 months. In all studies, overall survival was 100% at 24 and 36 months. Event-free survival was 97% in the United States and 100% in the United Kingdom at 12 months. At 24 months, 90% of patients in the United States no longer needed immunoglobulin therapy, while at 36 months, 100% of patients in the United Kingdom had stopped replacement therapy. There were no reported cases of monoclonal expansion, oncogenic adverse events, or replication of pathogenic lentivirus. Furthermore, no reports of autoimmunity or graft-versus-host emerged. The most common adverse events were infections, pyrexia, and gastrointestinal events. Overall, this study demonstrated the feasibility of using ex vivo edited autologous CD34+ HSPCs for ADA-SCID treatment.

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