Preclinical efficacy and safety of a novel lentiviral vector for ex vivo gene therapy of p47phox-deficient chronic granulomatous disease

Chronic granulomatous disease is a primary immunodeficiency caused by mutations in the genes encoding subunits of the nicotinamide adenine dinucleotide phosphate oxidase complex, resulting in impaired antimicrobial activity of phagocytes. Patients suffer from recurrent infections and inflammation with life-threatening long-term complications. We developed a self-inactivating lentiviral vector for ex vivo gene therapy of p47phox-deficient chronic granulomatous disease, expressing p47phox under control of the myeloid-specific miR223 promoter. Our preclinical studies using the p47phox-deficient mouse model of the disease showed that transduced hematopoietic stem cells engrafted well and led to sustained p47phox expression and NADPH oxidase function in myeloid cells, demonstrating myeloid-specific long-term efficacy. An average of 2 vector integrations per cell were sufficient to restore p47phox expression and NADPH oxidase activity in ∼80% of blood granulocytes. Physiological biodistribution of transduced cells and absence of transgene-related toxicity confirmed the safety of the vector. Transduction of human healthy donor and patient hematopoietic stem and progenitor cells showed that an average of 2 integrations per cell were sufficient to restore NADPH oxidase activity in a clinically relevant 40% of in vitro generated phagocytes. Overall, our preclinical results confirmed the efficacy and safety of this lentiviral vector, supporting translation into a first-in-human clinical trial.

Abstract from PubMed (PMID 42995490). This entry was added automatically by our daily literature monitor because it matches the topics we follow; read the full paper at the original source.