Single-Stranded Oligonucleotide Aptamer Binding to P-Selectin Inhibits Adhesion of Sickle Red Blood Cells and Leukocytes to Endothelial Cells in Sickle Cell Disease Model Mice: Novel Therapeutics for Vaso-occlusive Episodes

Abstract

Adhesive interactions between circulating red blood cells (RBC), leukocytes, and endothelial cells in post capillary venules have been implicated as a contributing factor to the pathogenesis of vaso-occlusion, the major cause of morbidity and mortality associated with sickle cell disease (SCD). Endothelial cell P-selectin, a member of the selectin family of cell adhesion molecules, plays a key role in leukocyte recruitment as well as in the adhesion of sickle RBC (sRBC) to the endothelium. The expression of P-selectin is elevated in SCD and the interaction of P-selectin and its ligands is likely to contribute to impairment of the microvascular flow and thereby to the development of painful vaso-occlusive episodes. Aptamers, short single-stranded oligonucleotides that fold into complex 3-D structures and bind to ligands, have been developed for a wide range of therapeutic targets. Although anti-P-selectin aptamers have been shown to inhibit leukocyte rolling in vitro and to display efficacy in mouse models for inflammation, anti-adhesion activity of anti-P-selectin aptamers has never been evaluated in SCD.