Regulating Transcriptional Co-Activator PGC-1α for the Treatment of Sickle Cell Disease

Abstract Sickle cell disease (SCD) is the most common inherited human hematologic disease, which causes hemolytic anemia, pain, disability, progressive multi-organ damage and early mortality. Clinical studies have shown that increased synthesis of fetal hemoglobin (HbF) in sickled erythroid cells leads to diminished severity of many clinical features of SCD. Therefore, therapeutic agents that can increase HbF production will be of benefit to SCD patients. Hydroxyurea (HU) is the FDA-approved therapeutic for treatment of SCD, but not all patients respond favorably or adequately. Therefore, other methods of targeting HbF are highly desired, particularly those that act by different mechanisms that might be used in combination with HU or alone (for those who do not tolerate HU). We recently identified PPARγ co-activator (PGC-1α) as a new protein involved in the regulation of the fetal globin genes. Forced overexpression of PGC-1α in vitro by adenovirus infection in bone marrow cells from SCD mice resulted in significantly increased human γ- and murine εy- and βh1-globin genes. Furthermore, up-regulation of PGC-1α by a small molecular agonist (Compound Z) in human umbilical cord blood-derived erythroid progenitor (HUDEP-1) cells markedly increases γ-globin gene expression and HbF synthesis. The highest response was achieved when HUDEP-1 cells were treated with 5µM Compound Z for 2 days, which results in 66.6% HbF+ cells compared to vehicle control (29.5% HbF+ cells). The effect of Compound Z in inducing HbF was further validated in erythroblasts derived from cultures of normal adults' CD34+ cells as well as in iPSC-derived sickle erythroblasts (SS24 cells). These data suggest that modulating PGC-1α activity may be effectively applied to the treatment of SCD since enhanced HbF synthesis would alleviate pathophysiological effects of SCD. Disclosures No relevant conflicts of interest to declare.