New Therapeutic Options for the Treatment of Sickle Cell Disease

Abstract

Sickle cell disease (SCD; ORPHA232; OMIM # 603903) is a chronic and invalidating disorder distributed worldwide, with high morbidity and mortality. Given the disease complexity and the multiplicity of pathophysiological targets, development of new therapeutic options is critical, despite the positive effects of hydroxyurea (HU), for many years the only approved drug for SCD. New therapeutic strategies might be divided into (1) pathophysiology-related novel therapies and (2) innovations in curative therapeutic options such as hematopoietic stem cell transplantation and gene therapy. The pathophysiology related novel therapies are: a) Agents which reduce sickling or prevent sickle red cell dehydration; b) Agents targeting SCD vasculopathy and sickle cell-endothelial adhesive events; c) Anti-oxidant agents. This review highlights new therapeutic strategies in SCD and discusses future developments, research implications, and possible innovative clinical trials.

Keywords: Hemoglobinopathy; Hydroxyurea; Selectin inhibitors; Sickle cell disease; Vaso-occlusive events.

Figure 1

Schematic diagram of the mechanisms involved in the pathogenesis of acute sickle cell related vaso-occlusive events. These involve the adherence of sickle red blood cells (RBCs) or reticulocytes and neutrophils to the abnormally activated endothelial cells, with the participation of activated and phosphatidyl- Serine (PS)-rich platelets (PLTs), activation of the coagulation system, and activation of a cytokine storm. PS: Phosphatidyl-Serine; TSP: thrombospondine; vWF: von Willebrand factor; BCAM/LU: Lutheran blood group protein; ICAM-4: Landstein-Weiner (LW) blood group glycoprotein; MPs: microparticles; Mac1: β2 integrins (α_Mβ₂ or CD11b/CD18); ESL-1: neutrophil E-selectin ligand -1; Hb: hemoglobin; ROS: reactive oxygen species; iNKT: invariant natural killer T cells; ET-1: endothelin-1; NO: nitric oxide (modified from De Franceschi L et al. Seminars in Thrombosis, 37: 266; 2011).

Figure 2

Schematic diagram of multimodal therapeutic action of hydroxyurea (HU) in sickle cell disease. ROS: reactive oxygen species; Hb: hemoglobin; NO: nitric oxide; HbS: sickle hemoglobin; HbF: fetal hemoglobin.

Figure 3

Schematic diagram of the mechanisms of action of pathophysiology based new therapeutic options for treatment of sickle cell disease and sickle cell vasculopathy. Hp: haptoglobin; Hx: hemopexin; NAC: N-Acetyl-cysteine; Ab: antibody; ROS: reactive oxygen species; iNKT: invariant natural killer T cells; NKTT120: humanized monoclonal antibody specifically depleting iNKT; NO: nitric oxide; ET-1: endothelin-1; ET-R: endothelin-1 receptor.