Abstract
Sickle cell disease (SCD) is a genetic disorder that affects millions around the world. Enhancement of fetal γ-globin levels and fetal haemoglobin (HbF) production in SCD patients leads to diminished severity of many clinical features of the disease. We recently identified the transcriptional co-activator PGC-1α as a new protein involved in the regulation of the globin genes. Here, we report that upregulation of PGC-1α by infection with a lentivirus expressing PGC-1α or by the small-molecule PGC-1α agonist ZLN005 in human primary erythroid progenitor CD34
cells induces both fetal γ-globin mRNA and protein expression as well as the percentage of HbF-positive cell (F cells) without significantly affecting cell proliferation and differentiation. We further found that the combination of ZLN005 and hydroxyurea (hydroxycarbamide) exhibited an additive effect on the expression of γ-globin and the generation of F cells from cultured CD34
cells. In addition, ZLN005 induced robust expression of the murine embryonic βh1-globin gene and to a lesser extent, human γ-globin gene expression in sickle mice. These findings suggest that activation of PGC-1α by ZLN005 might provide a new path for modulating HbF levels with potential therapeutic benefit in β-hemoglobinopathies.