Background: Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations in the hemoglobin β (HBb) gene locus, resulting in dysfunctional or diminished adult hemoglobin (HbA) production that is the root cause of the increased morbidity and mortality associated with these diseases. Individuals with SCD and β-thalassemias who harbor additional genetic alterations that maintain elevated fetal hemoglobin (HbF) expression during adulthood demonstrate improved disease prognosis or, at sufficient HbF amounts, restore normal hemoglobin functions and are asymptomatic. Elucidating the regulatory networks that control HbF expression is critical to the discovery of new therapies for SCD and β-thalassemia.
Aims: To elucidate the mechanism by which Polycomb Repressive Complex 2 regulates HbF expression
Methods: Genetic and pharmacologic targeting of PRC2 components in healthy and SCD CD34+ derived erythroid cells in vitro and wildtype and Townes HbSS in vivo models. RNA-sequencing was used to look at response to PRC2 modulation and impact on HbF levels.
Results: We show that modulation of PRC2 potently downregulates expression of master fetal hemoglobin regulator BCL11A, and thus is a putative upstream regulator of HBG gene expression. Specifically, we demonstrate negative modulation of PRC2 activity via multiple different pharmacologic or genetic knockdown approaches results in decreased expression of BCL11A and concomitant and robust increases in both HBG mRNA and HbF protein in vitro and in vivo. Downregulation of BCL11A is mechanistically distinct from the current standard of care, Hydroxyurea, and pre-clinical HbF induction via FTX-6058 exceeds that observed with Hydroxyurea.
Summary/Conclusion: These novel findings further elucidate the regulatory network that underlies fetal hemoglobin gene expression and has important implications for the use of inhibitors of PRC2 as potential therapies for SCD and β-thalassemia. The translation of these findings is underway as FTX-6058, an investigational, novel and potent inhibitor of Embryonic Ectoderm Development (EED), is currently being evaluated in clinical studies as a potential treatment for select hemoglobinopathies (NCT04586985, NCT05169580).