PGC-1a Agonism Induces Fetal Hemoglobin and Exerts Anti-Sickling Effects in Sickle Cell Disease

Sickle cell disease is a growing health burden afflicting millions around the world. Clinical observation and laboratory studies have shown that the severity of sickle cell disease is ameliorated in individuals who have elevated levels of fetal hemoglobin. However, pharmacologic induction of fetal hemoglobin sufficient to diminish clinical severity in sickle patients has been challenging. We recently found that up-regulation of PGC-1a can induce fetal hemoglobin synthesis in human primary erythroblasts. Here, we report that a small molecular compound SR-18292 increases PGC-1a leading to enhanced fetal hemoglobin expression in human erythroid cells or ß-YAC and sickle cell disease mice. Sickled red blood cells are significantly reduced and disease complications are alleviated in SR-18292-treated sickle mice. SR-18292, or agents in its class, could be a promising therapeutic for sickle cell disease. Overall design: The objective of the study was to identify a potent small molecule targeting PGC-1a (SR-18292) and evaluate whether SR-18292 can induce fetal hemoglobin synthesis in vitro and in vivo and reduce sickle cell disease-related symptoms in humanized SCD mice. In vitro, we measured the protein levels and mRNA levels of PGC-1a and ?-globin in human CD34+ cells treated with SR-18292 at different dosages as well as F-cells. In vivo, we evaluate the fetal hemoglobin induction in two mouse models: a model is ß-YAC mice (a generous gift from Dr. Stuart Orkin's group at Harvard University), which have the entire human ß-globin gene cluster knocked in; the other is sickle cell disease mice model, which carry the human sickle hemoglobin gene and present many phenotypic similarities. For the mouse study, we also measured the protein levels and mRNA levels of PGC-1a and ?-globin, as well as the F-cells. And in the sickle cell disease mice model, we also checked the SCD-related symptoms after SR-18292 treatment. All animal experiments were performed in strict accordance with the ethical guideline and were approved by Boston University Institutional Animal Care & Use Committee (IACUC). For all experiments, the number of replicates, statistical analysis and P value are reported in the figure legends or the following detailed experiments description.