Research in Sickle Cell Disease: From Bedside to Bench to Bedside

Abstract

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.

Figure 1.

The first documented observation of sickle-shaped red blood cells. Historical figure from 1910, taken from the publication by Herrick with title “Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia.” (Reproduced with permission from JAMA Intern Med. 1910;6:517–521. Copyright © 1910 American Medical Association. All rights reserved.)

Figure 2.

Pathophysiology of SCD. Polymerization of HbS under a state of deoxygenation is the fundamental event in the pathophysiology of SCD. These sickled RBCs become activated and interact via pro-inflammatory cytokines with the endothelium, WBCs, especially neutrophils/monocytes, and platelets. There is increased expression of pro-adhesive molecules (selectins) in the endothelial vasculature, which promote the adhesion of WBC, a key component of vaso-occlusion physiology. Platelet activation promotes further cytokine release and inflammation and also a hypercoagulable state by secreting coagulation and tissue factors. These damaged “sickle” RBCs are prone to destruction, leading to the continual release of cell-free hemoglobin which leads to depletion of hemopexin and haptoglobin. Consequently, the bioavailability of nitric oxide is reduced, leading to vascular dysfunction and end-organ damage. Both pathways triggered by the polymerization of HbS perpetuate the chronic state of inflammation seen in SCD facilitating end-organ damage. ESL-1 = E-selectin ligand-1; HbS = hemoglobin S; NET = neutrophil extracellular trap; RBC = red blood cell; ROS = reactive oxygen species; SCD = sickle cell disease; WBC = white blood cell.