Towards modulator therapy for ADA2 deficiency

Human ADA2 deficiency is a rare inborn error of immunity caused by pathogenic variants in ADA2.

The disease has a wide array of presentations ranging from vasculitis of the skin to the central nervous system (with strokes), fevers and immunodeficiency to cytopenia and bone marrow failure. Mortality is 10%, and occurs mostly in childhood.

TNF inhibitor treatment is efficient for treating the vasculitis, but the bone marrow failure is refractory to treatment and requires hematopoietic stem cell transplantation (HSCT). In the context of DADA2, HSCT is complicated by graft failure in a high percentage of patients. Therefore, the treatment of cytopenia in DADA2 represents an urgent medical need.

This project is built on the discovery, made during the course of the ERC St Grant MORE2DADA2, that it is possible to restore ADA2 expression in missense mutant cells by drug intervention in vitro, providing a first layer of evidence for the possibility to use modulator therapy in ADA2 deficiency. Therefore in this project, we wish to identify additional modulators for ADA2.

Our goal is to identify drugs that are able to restore in part or completely the ADA2 expression and function as well as the transcriptomic and metabolomic signature of ADA2 mutant cells. The ultimate goal is to take these modulators to the DADA2 patients.