Sickle cell anemia (SCA) was first described in the Western literature more than 100 years ago. Elucidation of its molecular basis prompted numerous biochemical and genetic studies that have contributed to a better understanding of its pathophysiology. Unfortunately, the translation of such knowledge into developing treatments has been disproportionately slow and elusive. In the last 10 years, discovery of BCL11A, a major γ-globin gene repressor, has led to a better understanding of the switch from fetal to adult hemoglobin and a resurgence of efforts on exploring pharmacological and genetic/genomic approaches for reactivating fetal hemoglobin as possible therapeutic options. Alongside therapeutic reactivation of fetal hemoglobin, further understanding of stem cell transplantation and mixed chimerism as well as gene editing, and genomics have yielded very encouraging outcomes. Other advances have contributed to the FDA approval of three new medications in 2017 and 2019 for management of sickle cell disease, with several other drugs currently under development. In this review, we will focus on the most important advances in the last decade.
Sickle cell disease (SCD) is an exemplar of bidirectional translational research, starting with a remarkable astute observation of the abnormally shaped red blood cells that motivated decades of bench research that have now translated into new drugs and genetic therapies. Introduction of hydroxyurea (HU) therapy, the only SCD-modifying treatment for >30 years and now standard care, was initiated through another clinical observation by a pediatrician. While the clinical efficacy of HU is primarily due to its fetal hemoglobin (HbF) induction, the exact mechanism of how it increases HbF remains not fully understood. Unraveling of the molecular mechanism of how HU increases HbF has provided insights on the development of new HbF-reactivating agents in the pipeline. HU has other salutary effects, reduction of cellular adhesion to the vascular endothelium and inflammation, and dissecting these mechanisms has informed bench-both cellular and animal-research for development of the 3 recently approved agents: endari, voxelotor, and crizanlizumab; truly, a bidirectional bench to bedside translation. Decades of research to understand the mechanisms of fetal to adult hemoglobin have also culminated in promising anti-sickling genetic therapies and the first-in-human studies of reactivating an endogenous (γ-globin) gene HBG utilizing innovative genomic approaches.
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