Lentiviral Gene Therapy for X-Linked Chronic Granulomatous Disease

To assess the safety and evaluate the efficacy and stability of ex vivo autologous CD34+ hematopoietic stem and progenitor cell based lentiviral gene therapy for X-linked CGD.

This study included 9 male patients with X-CGD (confirmed by DNA sequencing and absent NADPH-oxidase activity) who lacked a 10/10 HLA-matched donor.

This is a multicenter prospective study to evaluate the safety and efficacy of lentiviral gene therapy for X-CGD. Patients’ clinical characteristics, laboratory findings (including dihydrorhodamine assay, superoxide assessment), vector integration studies and clinical outcomes were followed from baseline through 12–36 months follow-up.

Two of the nine patients (22%) died within three months of therapy due to complications from pre-existing conditions (thought to be unrelated to gene therapy). Seven patients had corrected circulating neutrophils within one month of therapy with DHR+ activity noted in >15% of neutrophils, and this was sustained at 1 year follow up in 86% of surviving patients. After 1 year, 86% of surviving patients had stable vector copy numbers and the sustained presence of 16% to 46% oxidase-positive neutrophils. There was also no evidence of transcriptional silencing of integrated vector genome or clonal expansion. Clinically, all 7 patients had no new CGD-related infections, and 86% of them were able to discontinue CGD-related prophylactic antibiotic or antifungal treatment. One patient has persistent chronic pulmonary fibrosis.

Autologous gene therapy is a promising effective therapeutic approach for severely affected patients with X-CGD.

Patients with X-CGD are at lifelong risk of recurrent life-threatening infections that greatly impacting their morbidity, mortality, and quality of life. Although allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for CGD, it is associated with the risk of GVHD and other alloreactive complications. These risks can be avoided by autologous hematopoietic stem cell (HSC) gene therapy. This is the first-in-human study of lentiviral HSC gene therapy with vector G1XCGD in patients with X-CGD. Study results were encouraging, with all surviving patients free of CGD-related infections and nearly all no longer requiring prophylactic antimicrobial agents. This article highlights a promising alternative curative treatment of X-CGD without an evidence of genotoxicity. Further studies are necessary to evaluate longer-term efficacy and safety of lentiviral gene therapy in patients with X-CGD.