Project description
Identifying drugs for adenosine deaminase 2 deficiency
Human adenosine deaminase 2 (ADA2) deficiency is a rare immune disorder caused by variants in the ADA2 gene, leading to symptoms such as vasculitis, strokes, immunodeficiency and bone marrow failure, with a mortality rate of 10 %, primarily in childhood. While tumour necrosis factor, or TNF, inhibitors help manage vasculitis, haematopoietic stem cell transplantation is often complicated by graft failure. Recent research indicates that certain drugs can restore ADA2 expression in vitro, highlighting the potential for modulator therapy. The ERC-funded MODULATEDADA2 project will identify additional modulators for ADA2, aiming to discover drugs that can partially or fully restore ADA2 expression and function, as well as the transcriptomic and metabolomic profiles of cells with ADA2 mutations. These modulators are intended for therapeutic use.
Objective
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.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- social sciencessociologydemographymortality
- medical and health sciencesbasic medicineneurologystroke
- medical and health sciencesclinical medicinetransplantation
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Keywords
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Funding Scheme
HORIZON-ERC-POC - HORIZON ERC Proof of Concept GrantsHost institution
3000 Leuven
Belgium