ERA-Net E-Rare

Chronic granulomatous disease (CGD) is a rare, life-threatening inherited disorder of the phagocytes characterized by the absence of NADPH oxidase activity. CGD patients show a high susceptibility to infections and an excessive inflammatory response; their treatment remains a challenge due to the high prevalence of complications. Hematopoietic stem cell gene therapy has provided clinical benefits to patients, but the current vector technology has important safety limitations. The main objectives of this project are to provide more insights into the molecular basis and pathogenesis of clinical manifestations of different genetic variants of CGD and to develop safer therapeutic approaches based on innovative gene transfer technology. This network integrates the competence of different scientists and physicians on CGD and the use of advanced technology at the European level. The first aim will be to study the genotype-phenotype correlation in a large cohort of patients from different European countries with specific mutations. The second goal is to improve the understanding of the pathogenesis of the inflammatory and autoimmune manifestations by characterizing the immunological profile of CGD patients. The final goal is to develop a novel gene transfer approach into HSC for the gp91phox- and p47phox-deficient variants of CGD. To allow safe and controlled expression of the therapeutic genes, lentiviral vectors containing myeloid-specific promoters and/or microRNA target elements will be designed and tested in murine models of the disease as well as in CGD patients’ cell.