Therapeutic strategies to ameliorate heme-driven tissue oxidative injury in sickle cell anemia

Sickle cell disease (SCD) is a genetic anaemia characterized by an enhanced lysis of red blood cells resulting in the release of hemoglobin into the bloodstream. Hemoglobin-derived heme strongly contributes to vessels and tissues damage responsible for episodes of pain ranging from mild to severe and resulting, at times, fatal. This project is aimed at establishing a new therapy based on the idea that promoting heme loss through the bile may prevent heme-driven tissue injury. Therefore we will study the heme exporter FLVCR1 (Feline Leukemia Virus subgroup C Receptor) which is the strongest candidate for the role of heme transporter from the hepatocyte to the bile. We will analyze the consequences of FLVCR1 loss in a mouse model of SCD to establish its role in heme detoxification. Then, we will develop a system to enhance FLVCR1 expression in SCD and we will evaluate if FLVCR1-overexpressing sickle mice are protected from tissue damage and hemolytic crisis. Finally, this system will be used in association with a therapy promoting heme delivery to the liver, which we have already shown to be beneficial for SCD mice. The results of this project may constitute the basis for the future development of new therapies that improve the health status and the quality of life of SCD patients.