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

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Schejtman, Andrea ; Aragao-Filho, Walmir Cutrim ; Clare, Simon ; Zinicola, Marta ; Weisser, Maren ; Burns, Siobhan O. ; Booth, Claire ; Gaspar, Hubert B. ; Thomas, David C. ; Condino-Neto, Antonio ; Thrasher, Adrian J. ; Santilli, Giorgia

• Document type: Journal article
• Source: Gene Therapy; v. 27, n. 9, p. 11-pg., 2020-06-12.

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 inNCF1, which encodes the p47(phox)cytosolic component of the enzymatic complex. We generated a pCCLCHIM-p47(phox)lentiviral vector, containing the chimericCathepsin G/FESmyeloid promoter and a codon-optimised version of the humanNCF1cDNA. 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 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-p47(phox)vector. (AU)

• FAPESP's process: 14/01962-3 - Development of a pCCLchim lentiviral vector for gene therapy of patients with chronic granulomatous disease due to p47-phox deficiency
• Grantee: Walmir Cutrim Aragão Filho
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/13110-4 - Development of a pCCLchim lentiviral vector for gene therapy of patients with chronic granulomatous disease due to p47-phox deficiency
• Grantee: Walmir Cutrim Aragão Filho
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor