Progress in treating chronic granulomatous disease

Abstract

Chronic granulomatous disease is a primary immunodeficiency due to a defect in one of six subunits that make up the nicotinamide adenine dinucleotide phosphate oxidase complex. The most commonly defective protein, gp91 phox , is inherited in an X-linked fashion; other defects have autosomal recessive inheritance. Bacterial and fungal infections are common presentations, although inflammatory complications are increasingly recognized as a significant cause of morbidity and are challenging to treat. Haematopoietic stem cell transplantation offers cure from the disease with improved quality of life; overall survival in the current era is around 85%, with most achieving long-term cure free of medication. More recently, gene therapy is emerging as an alternative approach. Results using gammaretroviral vectors were disappointing with genotoxicity and loss of efficacy, but preliminary results using lentiviral vectors are extremely encouraging.

De novo mutation of CYBB gene in a boy presenting as intra-abdominal infection of Burkholderia contaminans: a case report

“…The incidence of inflammatory complications in patients with XLR-CGD is twice as high as that in patients with AR-CGD [6,18]. Appropriate anti-inflammatory agents, mainly corticosteroids, can significantly improve the prognosis of patients with CGD, and do not appear to increase the bacterial infection risk [3]. The recommended initial dose of prednisone is 1 mg/ kg daily and to be given for an average of 2-3 weeks before being tapered over several months [19].…”

“…Defects in genes encoding various components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex are associated with a dysfunctional respiratory burst, which decreases the ability of phagocytes to kill catalase-positive bacteria and fungi [2]. Mutations in CYBB, CYBA, NCF1, NCF2, NCF4, and CYBC1 genes have been associated with CGD [3]. About 70% of CGD cases are caused by defects in the CYBB gene, which is located on the short arm of the X chromosome (Xp21.…”

The Multiple Faces of Nitric Oxide in Chronic Granulomatous Disease: A Comprehensive Update

“…The cost-benefit balance for the therapeutic use of IFN-γ is favorable, especially for patients with the X-linked variant and with a history of invasive aspergillosis. Despite the benefits, IFN-γ drug therapy does not prevent granuloma formation and does not appear to improve symptoms of chronic inflammation [ 139 ]. On the other hand, working with cells from CGD patients and murine models, it has been shown that the blockade of the IL-1β receptor restores autophagy and inhibits the activity of the inflammasome, generating beneficial effects such as the attenuation of inflammation, resistance to invasive aspergillosis, and improvement of symptoms typical of colitis [ 140 ].…”

“…Rapamycin, an mTOR inhibitor and autophagy restorer, is capable of reducing the release of pro-inflammatory cytokines. Thus, it has been suggested that combination therapy with Anakinra and Rapamycin can be used to treat the inflammatory complications present in CGD patients [ 139 ].…”

Raising the ‘Good’ Oxidants for Immune Protection

“…The variation in outcomes might be attributable to different pioglitazone dosage, or to the often required combination therapy with antibiotics and/or interferon IFN-g. Further studies are necessary to determine if pioglitazone will provide a therapeutic option for CGD patients, for example as adjuvant therapy in severe bacterial infections or as prophylaxis. At this point only hematopoietic stem cell transplantation, gene therapy or gene editing with CRISPR-Cas9 offer a cure for CGD (272).…”