Preclinical Optimization and Safety Studies of a New Lentiviral Gene Therapy for p47^phox-Deficient Chronic Granulomatous Disease

Abstract

Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47 phox -deficient CGD (p47 phox CGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34 + cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34 + cells derived from a p47 phox CGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47 phox CGD.

Gene therapy for inborn error of immunity – current status and future perspectives

“…Initial attempts at HSC GT for CGD using gRV platform were unsuccessful due to poor engraftment [61], insertional mutagenesis leading to myelodysplastic syndrome with monosomy 7 [62,63], and silencing of the transgene [62,63]. Follow-up data from the first 9 X-linked CGD patients treated with a new, safer, LV vector containing a chimeric promoter to preferentially drive transgene expression at high levels in myeloid cells [64][65][66][67], following myeloablative conditioning, showed 78% survival, no CGD-related infections posttreatment, and 67% of the patients could discontinue antibiotic prophylaxis [24 & ]. Adult patients deemed unsuitable for HSCT on the basis of poor clinical status and end organ damage have benefitted from GT in these trials, demonstrating the feasibility of this therapy in an older patient population in need of alternative treatments.…”