Circulating Endothelial Cells and Microvesicles as Biomarkers for Gene Therapy in Sickle Cell Disease

Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, resulting from a mutation in the ?-globin gene. The polymerization of hemoglobin S in SCD has significant pathophysiological consequences -- hemolysis, inflammation, oxidative stress, hypercoagulability and painful vaso-occlusive crises that promote endothelial and vascular dysfunction. The SCD vasculature reflects the endothelial/vascular dysfunction with an active, pro-inflammatory, procoagulant phenotype (1), increasing the number of circulating endothelial cells (CECs) and microvesicles (MVs) . Increased number and activation status of CECs and endothelial-derived MVs (EMVs) is accompanied by heightened expression of soluble adhesion molecules and coagulation markers. Additionally, since CECs and EMVs compositional change reflects the activation state of their endothelial cell origin, they are emerging as indicators of endothelial dysfunction (2-5). Previous studies have found that plasma CECs, MVs, soluble adhesion molecules, and coagulation factors are present at low levels in healthy subjects, but are elevated in a variety of systemic inflammatory diseases, including SCD (2, 3, 6-9). Therefore, CECs and EMVs are ideal biomarkers for diagnosis and prognosis of inflammatory disorders, giving them huge potential in diagnosing SCD severity. Standardizing and validating CECs and EMVs as biomarkers of disease modification aligns with the goals of the Cure Sickle Cell Initiative, providing a defined scientific methodology to track changes in the vascular endothelium following curative gene SCD therapy.