Proximity-based strategies
to degrade proteins have enormous therapeutic
potential in medicine, but the technologies are limited to proteins
for which small molecule ligands exist. The identification of such
ligands for therapeutically relevant but “undruggable”
proteins remains challenging. Herein, we employed yeast surface display
of synthetic nanobodies to identify a protein ligand selective for
BCL11A, a critical repressor of fetal globin gene transcription. Fusion
of the nanobody to a cell-permeant miniature protein and an E3 adaptor
creates a degrader that depletes cellular BCL11A in differentiated
primary erythroid precursor cells, thereby inducing the expression
of fetal hemoglobin, a modifier of clinical severity of sickle cell
disease and β-thalassemia. Our strategy provides a means of
fetal hemoglobin induction through reversible, temporal modulation
of BCL11A. Additionally, it establishes a new paradigm for the targeted
degradation of previously intractable proteins