TY - CHAP M1 - Book, Section TI - Pharmacologic Induction of Fetal Hemoglobin A1 - Kutlar, Abdullah A1 - A. Sheehan, Vivien A2 - Gladwin, Mark T. A2 - Kato, Gregory J. A2 - Novelli, Enrico M. PY - 2021 T2 - Sickle Cell Disease AB - The presence of fetal hemoglobin (HbF,α2γ2) is known to reduce the clinical complications of sickle cell disease (SCD). Pharmacologic agents able to induce HbF have been sought after for decades. Agnostic drug screens have been unsuccessful, and progress in identifying novel HbF-inducing agents was slowed by our limited understanding of γ-globin regulation. Our understanding of γ-globin induction was increased significantly by an unbiased genome-wide association study (GWAS) approach, which identified variants in the transcription factor B-cell lymphoma/leukemia 11A (BCL11A) and regulatory elements within the intergenic region HBS1L-MYB as associated with HbF levels. Functional studies subsequently established the roles of BCL11A, MYB, and KLF1 in γ-globin repression, and disruption of the BCL11A erythroid enhancer element is now a gene therapy target in >1 clinical trial. Gene therapy may provide a cure for SCD, either through HbF induction or correction of the causative mutation, but several technical and safety hurdles must be overcome before this therapy can be offered widely, particularly in low-resource countries, where 99% of individuals with SCD reside. Pharmacologic therapies to treat SCD are still needed, and hydroxyurea, developed for use in SCD almost 3 decades ago, remains the only widely used pharmacologic HbF inducer. SN - PB - McGraw-Hill Education CY - New York, NY Y2 - 2024/11/05 UR - hemonc.mhmedical.com/content.aspx?aid=1179338538 ER -