Beyond hydroxyurea: new and old drugs in the pipeline for sickle cell disease

Abstract

Despite Food and Drug Administration (FDA) approval of hydroxyurea to reduce the frequency of vaso-occlusive episodes, sickle cell disease (SCD) has continued to be treated primarily with analgesics for pain relief. However, elucidation of the multiple pathophysiologic mechanisms leading to vaso-occlusion and tissue injury in SCD has now resulted in a burgeoning effort to identify new treatment modalities to prevent or ameliorate the consequences of the disease. Development of new drugs as well as investigation of drugs previously used in other settings have targeted cell adhesion, inflammatory pathways, upregulation of hemoglobin F, hemoglobin polymerization and sickling, coagulation, and platelet activation. Although these efforts have not yet yielded drugs ready for FDA approval, several early studies have been extremely encouraging. Moreover, the marked increase in clinical pharmaceutical research addressing SCD and the new and old drugs in the pipeline make it reasonable to expect that we will soon have new treatments for SCD.

Figure 1

The sickle red blood cell (SS RBC) as source of multiple pathophysiologic pathways. Red cells with predominantly HbS (SS RBCs) become rapidly dehydrated, which increases the propensity of HbS to polymerize when deoxygenated. Pharmacologic reagents that prevent dehydration may therefore also reduce HbS polymerization and hemolysis. Altered lipid sidedness (phosphatidylserine exposure) may play a role in SS RBC adhesion and also promote activation of coagulation. Oxidative damage of red cell membrane proteins likely contributes to altered cell elasticity. Abnormal adhesive properties lead to SS RBC adhesion to endothelial cells (A), SS RBC adhesion to neutrophils (B), and adhesive interactions that result in heterocellular aggregate formation involving SS RBCs, monocytes, and platelets (C). Abnormal intracellular signaling increases the activation state of red cell adhesion molecules, and increased adhesive interactions then lead to abnormally active cell-cell signaling, which leads to activation of both other blood cells and endothelial cells. Both SS RBCs and hypoxia/reperfusion also lead to activation of inflammatory pathways involving both mononuclear and polymorphonuclear leukocytes. Platelet activation also contributes to inflammatory pathways as well as activation of coagulation.

Figure 2

Adhesive interactions involving SS RBCs. (A) Multiple interactions between SS RBCs and endothelial cells, extracellular matrix, and plasma proteins. Red cells express multiple adhesion molecules that recognize ligands on either plasma protein “bridging molecules” or endothelial cell surfaces. Specific adhesion receptors on red cells that contribute to vaso-occlusion include ICAM-4 (the LW blood group protein, a receptor for several integrins), BCAM/Lu (the Lutheran blood group protein, a receptor for laminins (LAM) containing the α5 chain [laminins-10 and -11]), and CD44 (which bears the Indian blood group antigens), which is involved in binding to fibronectin and E-selectin. SA, sialic acid; FBN, fibronectin; TSP, thrombospondin; ULvWF, ultra-large von Willebrand factor. (B) Interactions between SS RBCs and leukocytes adherent to vessel walls. Many stimuli may activate leukocyte adhesion, including cytokines and contact with SS RBCs. Adhesion to endothelial cells initially occurs via selectins expressed by endothelial cells but ultimately likely also involves endothelial integrins. ESL-1, E-selectin ligand-1; PSGL-1, P-selectin glycoprotein ligand-1.