Lentiviral gene therapy rescues p47^phox chronic granulomatous disease and the ability to fight Salmonella infection in mice.

ABSTRACT: 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.

SUBMITTER: Schejtman A 

PROVIDER: S-EPMC7500983 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature