METHODS FOR SCREENING DRUGS FOR THE TREATMENT OF SICKLE CELL DISEASE

摘要

Sickle cell disease (SCD) is a group of disorders that affects hemoglobin (Hb), the molecule in red blood cells that delivers oxygen to cells throughout the body. People with this disorder have atypical Hb molecules called hemoglobin S (HbS) and suffers from chronic and acute hemolysis that is responsible for the release of free Hb and heme in the circulation. A recent study suggests that heme triggers TLR4 signaling leading to endothelial cell activation, increased activated leukocytes and platelets adhesion and vaso-occlusion. However this mechanism is not totally satisfactory considering that other hemolytic conditions (such as thalassemia major or spherocytosis), wherein heme is also released, do not lead to cell activation, inflammation and vaso-occlusion. Now the inventors show that HbS, but not HbA, triggers a TRL-4 signaling that leads to the production of inflammatory cytokines by monocytes. Accordingly, inhibiting said signaling would be suitable for the treatment of SCD in particular for the treatment of vaso-occlusions and acute chest syndromes.