PGC-1α agonism via oral administration of ZLN005 induces fetal hemoglobin and is antisickling in sickle mice.

Sickle cell disease (SCD), caused by a point mutation in the β-globin gene (HBB), results in the production of sickle hemoglobin (HbS). Deoxy-HbS polymerizes, deforming red blood cells (RBCs) and leading to a cascade of clinical complications, including vaso-occlusion, hemolysis, inflammation, and progressive organ damage. An effective strategy to mitigate disease severity is the reactivation of fetal hemoglobin (HbF), which interferes with HbS polymerization. We explored the therapeutic potential of ZLN005, a small-molecule activator of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-α), by evaluating its impact on HbF induction in CD34+ hematopoietic progenitor cells derived from patients with SCD, in β-YAC transgenic mice carrying a normal human HBB cluster, and in SCD mice. ZLN005 increased γ-globin expression and HbF+ cells without impairing erythroid differentiation of CD34+ cells. Oral administration of ZLN005 to SCD mice increased HbF+ cells, reduced sickled RBCs, increased hemoglobin levels, lowered reticulocyte counts, and decreased spleen and liver pathology related to SCD. ZLN005 or related compounds could represent a promising new class of orally available HbF-inducing therapeutics.