Work

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

Year: 2020

Type: article

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 gp91phoxsubunit of the NADPH oxidase. We propose to use a similar strategy to tackle p47phox-deficient CGD, caused by mutations inNCF1, which encodes the p47phoxcytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47phoxlentiviral vector, containing the chimericCathepsin G/FESmyeloid promoter and a codon-optimised version of the humanNCF1cDNA. Here we show that transduction with the pCCLCHIM-p47phoxvector efficiently restores p47phoxexpression and biochemical NADPH oxidase function in p47phox-deficient human and murine cells. We also tested the ability of our gene therapy approach to control infection by challenging p47phox-null mice withSalmonellaTyphimurium, 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-p47phoxvector.

Source: Gene Therapy

DOI: 10.1038/s41434-020-0164-6