Strategies for gene therapy for SCD: schematic overview of various approaches for correcting the sickle phenotype via gene therapy. Gene correction: targeted genome engineering leads to correction of the sickle mutation such that β^S is repaired as β^A. HbF induction: multiple strategies for induction of γ-globin expression include shRNA-mediated knockdown of BCL11A, targeted disruption of the +58 DNase I HS site in the BCL11A erythroid-specific enhancer, and forced chromatin looping to promote association of the β-globin LCR with the γ-globin genes. Gene addition: integrating lentiviral vector carrying a β-globin, γ-globin, or antisickling β-globin cassette. Ldb1, transcription factor; ZF/SA, zinc-finger self-association domain.