Understanding the pathogenesis and developing better therapies for adenosine deaminase 2 deficiency

Adenosine deaminase 2 deficiency, or DADA2, is a rare genetic disorder caused by autosomal recessive mutations in the ADA2 gene. A prevalence study estimated that 1 in 222,164 people could have DADA2. This means that there are over 30,000 people with DADA2 around the world. Clinical presentations include cutaneous and cerebral vascular disease, stroke, systemic inflammation, and cytopenia (the lack of one or more types of blood cells). The onset of the disease generally occurs in childhood, and a significant percentage (about 8%) of patients with DADA2, if not diagnosed and treated, die within 30 years. Specific treatments for DADA2 are currently unavailable, and the clinical benefit of existing treatments is unsatisfactory. Anti-TNF therapy, used as a first-line treatment, reduces the incidence of stroke but is not curative and does not correct cytopenia. Allogeneic hematopoietic progenitor stem cell (HSPC) transplantation has been successfully applied in some patients. Unfortunately, this therapy is not without risk and is only available to those patients who have a compatible donor. Hence, there is a tremendous need for DADA2 therapies to achieve significant and sustained clinical outcomes. To date, the mechanisms responsible for DADA2 are not fully understood, as the disease was only recently discovered. This project aims to identify the cellular and molecular mechanisms underlying the pathology of DADA2 and develop innovative therapies mediated by autologous HSPCs genetically corrected ex vivo with a lentiviral vector expressing ADA2.