Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects

• Published in: Pediatric allergy and immunology Vol. 27; no. 3; pp. 242 - 253
• Main Authors: Chiriaco, Maria, Salfa, Irene, Di Matteo, Gigliola, Rossi, Paolo, Finocchi, Andrea
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2016; Wiley Subscription Services, Inc
• Subjects: Anti-Infective Agents - therapeutic use; chronic granulomatous disease; Disease; Genes; genetic counseling; Genetic Therapy - methods; Granulomatous Disease, Chronic - diagnosis; Granulomatous Disease, Chronic - genetics; Granulomatous Disease, Chronic - therapy; Hematopoietic Stem Cell Transplantation - methods; Humans; hyperinflammation; Immune system; infections; molecular diagnosis; Mutation; NADPH oxidase; NADPH Oxidases - genetics; Rodents; therapy; genetic counseling; NADPH oxidase; chronic granulomatous disease; therapy; infections; hyperinflammation; molecular diagnosis
• ISSN: 0905-6157; 1399-3038
• DOI: 10.1111/pai.12527

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by defects in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. CGD is a genetically heterogeneous disease with an X‐linked recessive (XR‐CGD) form caused by mutations in the CYBB gene encoding the gp91phox protein, and an autosomal recessive (AR‐CGD) form caused by mutations in the CYBA, NCF1, NCF2, or NCF4 genes encoding p22phox, p47phox, p67phox, and p40phox, respectively. Patients suffering from this disease are susceptible to severe life‐threatening bacterial and fungal infections and excessive inflammation characterized by granuloma formation in any organ, for instance, the gastrointestinal and genitourinary tract. An early diagnosis of and the prompt treatment for these conditions are crucial for an optimal outcome of affected patients. To prevent infections, CGD patients should receive lifelong antibiotics and antifungal prophylaxis. These two measures, as well as newer more effective antimicrobials, have significantly modified the natural history of CGD, resulting in a remarkable change in overall survival, which is now around 90%, reaching well into adulthood. At present, hematopoietic stem cell transplantation (HSCT) is the only definitive treatment that can cure CGD and reverse organ dysfunction. Timing, donor selection, and conditioning regimens remain the key points of this therapy. In recent years, gene therapy (GT) for XR‐CGD has been proposed as an alternative to HSCT for CGD patients without a matched donor. After the failure of the first trials performed with retroviral vectors, some groups have proposed the use of regulated SIN‐lentiviral vectors targeting gp91phox expression in myeloid cells to increase the safety and efficacy of the GT protocols.