Chronic granulomatous disease (CGD) is a rare inherited disorder of the phagocytes caused by absence of NADPH oxidase activity and characterized by the inability of monocytes and neutrophils to produce reactive oxygen (O2) species in response to stimuli.
CGD is a debilitating primary immunodeficiency (PID).
The NADPH oxidase consists of five subunits, all of which can contain mutations leading to CGD. In the X-linked recessive form (65% of cases) the mutations are localized in the CYBB gene (encoding gp91phox) on chromosome Xp21.1 (MIM ID #306400). Affected patients present an elevated susceptibility to bacterial and fungal infections, as well as an excessive inflammatory response leading to granuloma formation. Invasive aspergillosis is the leading cause of death in patients with CGD.
Conventional treatment of CGD consists of lifelong prophylaxis with antibiotics , anti-mycotics and/or interferon gamma. Overall, these prophylactic measures ameliorate the symptoms of the disease, as reflected by improved health and survival. Patients with life-threatening episodes of antimicrobial therapy-refractory infections can be temporarily supported by allogeneic granulocyte infusions, although limited by the risk of antibody formation against foreign HLA-antigens and other reactions. To date, haematopoietic stem cell transplantation (HSCT) with a suitable donor is the only established option for permanent cure of CGD.
However, at least one third of patients do not have an HLA-matched compatible donor, and HSCT in these patients is associated with high morbidity and mortality.
Gene therapy may represent a definitive cure for CGD patients for whom conventional HSCT is not possible.