PGC-1α Agonism via Oral Administration of ZLN005 Induces Fetal Hemoglobin and is Anti-Sickling in Sickle Mice

Sickle cell disease (SCD) caused by a point mutation in the β-globin gene results in the production of sickle hemoglobin (HbS). DeoxyHbS 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, by evaluating its impact on HbF induction in CD34⁺ hematopoietic progenitor cells derived from SCD patients, in β-YAC transgenic mice carrying a normal human β-globin gene cluster, and in SCD mice. ZLN005 increased γ-globin expression and F-cells without impairing erythroid differentiation of CD34+ cells. Oral administration of ZLN005 to sickle mice increased F-cells, reduced sickled RBCs, increased hemoglobin levels, lowered reticulocyte counts, and decreased sickle cell-related spleen and liver pathology. ZLN005 or related compounds could represent a promising new class of orally available HbF-inducing therapeutics.