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Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency disorder characterised by recurrent and often life-threatening infections and hyperinflammation. It is caused by defects of the phagocytic NADPH oxidase, a multicomponent enzyme system responsible for effective pathogen killing. A phase I/II clinical trial of lentiviral gene therapy is underway for the most common form of CGD, X-linked, caused by mutations in the gp91 phox subunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47 phox -deficient CGD, caused by mutations in NCF1, which encodes the p47 phox cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47 phox lentiviral vector, containing the chimeric Cathepsin G/FES myeloid promoter and a codon-optimised version of the human NCF1 cDNA. Here we show that transduction with the pCCLCHIM-p47 phox vector efficiently restores p47 phox expression and biochemical NADPH oxidase function in p47 phox -deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47 phox -null mice with Salmonella Typhimurium, a leading cause of sepsis in CGD patients, and found that mice reconstituted with lentivirus-transduced hematopoietic stem cells had a reduced bacterial load compared with untreated mice. Overall, our results potentially support the clinical development of a gene therapy approach using the pCCLCHIM-p47 phox vector.

Lentiviral gene therapy rescues p47phox chronic granulomatous disease and the ability to fight Salmonella infection in mice