Targeted protein degraders for the treatment of b-hemoglobinopathies - Globally, 300,000 babies are born annually with Sickle Cell Disease (SCD). Current therapies for SCD revolve around induction of fetal hemoglobin (HbF), as it critically antagonizes red blood cell sickling. For example, hydroxyurea, a ribonucleotide reductase inhibitor, increases HbF levels. While hydroxyurea is the standard of care treatment for prevention of sickle cell crises, its effect on HbF induction can be weak and is variable from patient to patient. Attention has recently shifted to targeted gene therapy and gene editing efforts. For example, CASGEVY™ is a CRISPR-Cas9 gene editing technique to disable an erythroid specific enhancer of BCL11A to reactivate fetal hemoglobin gene expression and thus, HbF production. However, gene therapies carry significant medical risks and costs in the millions per patient. Therefore, therapeutic development efforts to discover new small molecule HbF inducers are still necessary. Here, based on a substantial amount of preliminary data, we propose to develop orally bioavailable degraders of two fetal hemoglobin gene repressors in order to elevate HbF levels and prevent erythroid sickling to treat SCD. This proposal benefits from the strong complementary expertise and track record of the two collaborating laboratories.