EPIOX

Gain-of-function mutations in the mechanotransductor Piezo1 are involved in more than 90% of hereditary xerocytosis (XH), a rare hemolytic pathology which physiopathology is not well understood until now. We published in 2019 the largest series of patients and described precisely their clinical and biological phenotype, associating venous and arterial thrombosis occurring after splenectomy, hemolysis (quasi-constant), iron overload occurring independently of any transfusion and finally perinatal edema. For a long time, XH has been perceived as an essentially "mature red cell" pathology, but a growing number of data have shown an expression and function of PIEZO1 in other cell types than erythrocytes, including lymphatic valves, endothelial cells, macrophages, megakaryocytes and platelets, and erythroid precursors. Our hypothesis is that the phenotype of patients with hereditary xerocytosis reflects an abnormal expression/function of mutated PIEZO1 in these different cell types. We propose a collaborative project involving a diagnostic reference centre and four research laboratories to study the expression and function of PIEZO1 and the consequences of its pathological activation in the cellular systems impacted in HX. The first step of this project will be the phenotypic characterisation of patients and the functional study of the identified mutations, by electrophysiology, carried out in the laboratory of Dr Shang Ma, an international expert in this field. The consequences of these mutations leading to abnormal activation of PIEZO1 will then be studied in three systems: (i) erythropoiesis and the red blood cell (haemolysis, dyserythropoiesis) (ii) megakaryocytes, platelets and endothelial cells (frequent thrombosis after splenectomy) (iii) enterocytes, which may be involved in the iron overload described in these patients. Each of these tasks will be led by a specialist in the theme, in close interaction with the other members of the consortium. The research teams will share three experimental models: (i) haematopoietic, endothelial and enterocytic cells cultivated in vitro and in which the activation and expression of PIEZO1 will be modulated, (ii) primary haematopoietic cells from patients and (iii) a knock-in mouse model reproducing the recurrent gain-of-function R2456H mutation described in the patients, already generated by one of the partners. This collaborative project based on complementary expertise and shared tools will allow, via an original multi-systemic approach, the identification of new therapeutic targets for patients for whom treatment options are still lacking. The consortium attaches a particular importance to share the results with patients that will be recruited in the bi-centric clinical trial and included in the COStho cohort, led by one of the partners. These patients will be actively involved in the progress of the research through an annual virtual meeting organised by the consortium.