Pociredir inhibits polycomb repressive complex 2 and induces fetal hemoglobin in healthy and sickle cell disease models [dataset 2]

Moreover, we demonstrate that negative modulation of PRC2 activity via different pharmacologic or genetic knockdown approaches results in decreased BCL11A expression and concomitant and robust increases in both HBG1/2 mRNA and HbF protein (or their orthologs) across in vitro and in vivo models of SCD. These novel findings further elucidate the regulatory network underlying HBG1/2 expression and have important implications for the use of PRC2 inhibitors as potential therapies for SCD and b-thalassemias.

Inhibition of embryonic ectoderm development (EED), a key subunit of PRC2, was particularly effective in modulating the activity of the complex. The translation of these findings is underway as pociredir (FTX-6058), a novel and potent EED inhibitor, is currently being evaluated in clinical studies as a potential treatment for select hemoglobinopathies (NCT05169580).