Study of disease pathogenesis and development of gene therapy for adenosine deaminase 2 deficiency

Adenosine deaminase 2 deficiency (DADA2) is a rare genetic disease caused by autosomal recessive mutations in the ADA2 (formerly known as CECR1) gene. The most common presentation of DADA2 is cutaneous and cerebral vasculopathy, stroke, systemic inflammation, hematological and immunological manifestations. Disease onset is usually in childhood, and a significant proportion (~8%) of DADA2 patients are deceased before the age of 30. Targeted treatments are currently unavailable, and the clinical benefit of the existing treatments is variable. Anti-TNF therapy is used as a front-line treatment for DADA2, but the clinical benefit is variable, and a lifelong treatment may be ethically and economically challenging for most of the patients. Also, allogeneic hematopoietic stem-progenitor cell (HSPC) transplantation has produced encouraging results in a small cohort of DADA2 patients with the hematological phenotype, but several problems have arisen, including graft versus host disease, veno-occlusive disease, organ toxicity, and infections. Thus, the development of targeted therapeutical approaches for DADA2 is urgently needed. To date, the mechanisms responsible for DADA2 are not fully understood, as the disease was only recently discovered. The objectives of this project are the identification of the cellular and molecular mechanisms underlying the pathology of DADA2, and the development of innovative therapies mediated by hematopoietic stem cells genetically corrected ex vivo with a lentiviral vector expressing ADA2 and through genome editing.