Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects

Maria Chiriaco, Irene Salfa, Gigliola Di Matteo, Paolo Rossi, Andrea Finocchi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalPediatric Allergy and Immunology
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Chronic Granulomatous Disease
Therapeutics
Hematopoietic Stem Cell Transplantation
Genetic Therapy
Genes
Donor Selection
Mutation
Respiratory Burst
Antibiotic Prophylaxis
Mycoses
NADPH Oxidase
Myeloid Cells
Granuloma
Bacterial Infections
Gastrointestinal Tract
Early Diagnosis
Leukocytes
Tissue Donors
Inflammation
Safety

Keywords

  • Chronic granulomatous disease
  • Genetic counseling
  • Hyperinflammation
  • Infections
  • Molecular diagnosis
  • NADPH oxidase
  • Therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Pediatrics, Perinatology, and Child Health
  • Immunology

Cite this

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title = "Chronic granulomatous disease: Clinical, molecular, and therapeutic aspects",
abstract = "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.",
keywords = "Chronic granulomatous disease, Genetic counseling, Hyperinflammation, Infections, Molecular diagnosis, NADPH oxidase, Therapy",
author = "Maria Chiriaco and Irene Salfa and {Di Matteo}, Gigliola and Paolo Rossi and Andrea Finocchi",
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AU - Chiriaco, Maria

AU - Salfa, Irene

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AU - Finocchi, Andrea

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