4.2 Article

Chronic Granulomatous Disease: Lessons from a Rare Disorder

期刊

BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION
卷 17, 期 1, 页码 S123-S131

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ELSEVIER SCIENCE INC
DOI: 10.1016/j.bbmt.2010.09.008

关键词

Chronic granulomatous disease; NADPH oxidase; Hematopoietic cell transplantation; Gene therapy

资金

  1. NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [ZIAAI000991, ZIAAI000644, ZIAAI000645, ZIAAI000988, U54AI082973] Funding Source: NIH RePORTER
  2. NIAID NIH HHS [U54 AI082973, U54 AI082973-01] Funding Source: Medline
  3. Great Ormond Street Hospital Childrens Charity [V0904] Funding Source: researchfish

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Chronic granulomatous disease (CGD) is a rare primary immunodeficiency with X-linked or autosomal recessive inheritance involving defects in genes encoding phox proteins, which are the subunits of the phagocyte NADPH oxidase. This results in failure to produce superoxide anion and downstream antimicrobial oxidant metabolites and to activate antimicrobial proteases. Affected patients are susceptible to severe, life-threatening bacterial and fungal infections and excessive inflammation characterized by granulomatous enteritis resembling Crohn's disease and genitourinary obstruction. Early diagnosis of CGD and rapid treatment of infections are critical. Prophylaxis with antibacterial and mold-active antifungal agents and the administration of interferon-gamma has significantly improved the natural history of CGD. Currently, the only cure is allogeneic hematopoietic cell transplant (HCT), although there remains controversy as to which patients with CGD should get a transplant. Allele-based HLA typing of alternative donors, improved supportive care measures, and use of reduced toxicity conditioning have resulted in event-free survival (EFS) of at least 80% even with an unrelated donor and even better when the patient has no active infections/inflammation. Gene correction of CGD would eliminate the risks of graft-versus-host disease (GVHD) and the immunoablative chemotherapy required for allogeneic HCT. Based on gene therapy trials in patients with SCID-X1, ADA-SCID, and the early experience with CGD, it is clear that at least some degree of myeloablation will be necessary for CGD as there is no inherent selective growth advantage for gene-corrected cells. Current efforts for gene therapy focus on use of lentivector constructs, which are thought to be safer from the standpoint of insertional mutagenesis and more efficient in transducing hematopoietic stem cells (HSCs). Biol Blood Marrow Transplant 17: S123-S131 (2011) (C) 2011 American Society for Blood and Marrow Transplantation

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