Recent Advances in the Treatment of Sickle Cell Disease

Abstract

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.

Keywords: anti-sickling agents; gene editing; gene therapy; hemoglobinopathies; sickle cell disease.

FIGURE 1

Timeline review of historic events since the diagnosis of sickle cell disease with an emphasis over the last decade. SCD, sickle cell disease; HSCT, hematopoietic stem cell transplant; HU, hydroxyurea.

FIGURE 2

Schematic pathophysiology review of sickle cell disease and its main different targets for intervention. Hb S, hemoglobin S.

FIGURE 3

The different therapeutic approaches for sickle cell disease and their mechanisms and current status in clinical trials. Orange: targeting hemoglobin S polymerization; gray: targeting vasocclusion; light blue: targeting inflammation and green: modification of the genotype. shRNA, short hairpin RNA; Hb S, hemoglobin S; Hb F, hemoglobin F; PDE9, phosphodiesterase 9. *FDA approved July 2017; **FDA approved November 2019; ***Terminated in February 20, 2020 due to failure to meet primary endpoints.