New therapeutic approaches to sickle cell disease: Targeting RBC membrane oxidative damage

In this brief review, we discuss evidence leading to the conclusion that diminished levels of reduced glutathione combined with increased oxygen radical production leads to oxidative damage to membrane proteins in sickle cell disease erythrocytes. Among these oxidatively damaged proteins are K⁺- channels (Gardos channel and K⁺-Cl^--channel) and β-actin. Oxidative damage to the K⁺-channels leads to K⁺ leakage and H₂O loss from light density reversibly sickled cells (RSCs). The resulting dense RSCs are primarily sickled in shape due to increased [HbS] and increased polymerization. The oxidation of β-actin converts the dense RSCs to dense irreversibly sickled cells (ISCs) as explained in our two step model. Furthermore, we discuss recent in vitro evidence that N-acetylcysteine (NAC) can block the formation of dense cells and ISCs by protecting the K⁺-channels and β-actin respectively from oxidative damage. Finally we describe an ongoing Phase II human trial to determine whether NAC can also lower dense cells and ISCs in vivo and, if so, result in fewer painful vasooclusive episodes.