Project description
Insight into the pathophysiology of adenosine deaminase 2 deficiency
Adenosine deaminase 2 (ADA2) deficiency is an inherited disorder associated with abnormal inflammation throughout the body, including blood vessels (vasculitis), immunodeficiency, and cytopenia. However, many aspects of the pathophysiology of ADA2 deficiency remain unresolved. The scope of the EU-funded MORE2ADA2 project is to study the function of ADA2 and understand how it leads to disease characteristics and phenotype. Previous work by project researchers has shown a role of ADA2 in antiviral immune response and endothelial function. Moreover, scientists will screen novel drugs as alternative strategies to anti-TNF blockade and hematopoietic stem cell transplantation, which are the current first-line treatments.
Objective
Human adenosine type 2 (ADA2) deficiency is a rare but devastating condition resulting in a complex phenotype of vasculitis (ranging from cutaneous to intracerebral vasculitis with lacunar infarcts), immunodeficiency (recurrent bacterial or viral infections), bone marrow anomalies (cytopenia, aplasia), cancer (lymphoma, leukemia). Mortality is 10%, often in childhood. The mainstay of treatment consists of anti-TNF blockade for vasculitis. Cytopenia and immunodeficiency respond poorly. Hematopoietic stem cell transplantation is curative in most cases. Although the condition was described in 2014, its pathophysiology is unsolved. From previous work in my laboratory, I have gained insight that ADA2 is likely to play a significant role in antiviral host defense and endothelial function. I thus hypothesize that ADA2 deficiency is an underdiagnosed condition and that complete or partial ADA2 deficiency plays a role in several other common medical conditions. With this research proposal, I aim (1) to unravel the pathophysiology of ADA2 deficiency, to (2) study the significance of ADA2 deficiency in phenocopies of the disease (3) to study the function of ADA2 in vitro (4) to develop new treatment strategies for ADA2 deficiency and its phenocopies. To achieve these aims I will study the prevalence of ADA2 deficiency in cohorts of patients presenting with one or more of the main disease characteristics (e.g. juvenile stroke, aplasia, childhood lymphoma...) by genetic and functional approaches. The genotype, immunophenotype and clinical characteristics of these patients will be studied using the newest technologies. In cell lines and tissue samples of ADA2 deficient patients, we will study the function of ADA2. Finally, we will screen known and novel drugs for their potential use in ADA2 deficiency and phenocopies, even beyond, in cardiovascular disease, cancer, anti-viral host defense.
Fields of science
- medical and health sciencesbasic medicinephysiologypathophysiology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicinecardiologycardiovascular diseases
- medical and health sciencesclinical medicineoncologyleukemia
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Keywords
Programme(s)
Topic(s)
Funding Scheme
ERC-STG - Starting GrantHost institution
3000 Leuven
Belgium