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Blood, 15 April 2008, Vol. 111, No. 8, pp. 3918-3919.
Gardos pathway to sickle cell therapies?CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER
In this issue of Blood, Ataga and colleagues report that treatment of sickle cell disease patients with senicapoc, a Gardos channel inhibitor, reduces the number of dehydrated cells, increases hemoglobin levels, and diminishes hemolysis.
Sickle cell dehydration is thought to result from a complex interplay of Hb S polymerization and several cation transport systems in sickle cells. A transport pathway that normally regulates volume in reticulocytes, the potassium-chloride cotransporter (KCC) appears to function pathologically in sickle cells, overshooting its target hemoglobin concentration3 and priming the reticulocyte to sickle. Hb S polymerization activates a nonselective cation leak pathway in a fraction of sickle cells upon deoxygenation. Calcium entry via this sickling-induced pathway triggers activation of the Gardos channel, which mediates rapid KCl and water loss.4 Abnormal KCC activity in the sickle reticulocyte may thus facilitate a vicious spiral in which sickling and Gardos channel activation reinforce each other to dehydrate the cell. In vitro and animal studies have been insufficient, however, to elucidate how these pathways interact in vivo. Brugnara's pioneering clinical investigation of another Gardos channel blocker, clotrimazole,5 laid the foundation for the development of senicapoc. The demonstration in the current study that senicapoc reduces the number of dense sickle cells establishes conclusively that the Gardos pathway is active in vivo and contributes to sickle cell dehydration. Ataga and colleagues show that senicapoc treatment was well-tolerated, resulted in increased hemoglobin, and reduced markers of hemolysis—reticulocyte count, bilirubin, LDH levels—strongly suggesting that sickle cell survival was improved. Thus, the study demonstrates that prevention of dehydration in a clinical setting is feasible and decreases in vivo hemolysis in sickle disease. Recently, a phase 3 trial of senicapoc was terminated early because of low probability of achieving a reduction in crisis rate, the primary clinical end point.6 Laboratory endpoints of increased hemoglobin and reduced hemolysis confirmed the findings of the phase 2 study reported here. These results appear to reinforce clinical observations made decades ago that the number of dense (or irreversibly sickled) cells correlates with hemolysis7 but not with frequency of pain episodes.8 This is consistent with the concept that the hemolytic and vaso-occlusive components of sickle cell disease represent distinct, albeit interactive, pathophysiological mechanisms. The contribution of hemolysis to vasculopathy in sickle cell disease has been emphasized by demonstration of nitric oxide scavenging by plasma hemoglobin. Clinical complications associated with hemolysis include leg ulcers, priapism, stroke, and pulmonary hypertension, which, although insidious and gradual in onset, appears to be a major cause of death in sickle cell disease.9
Gardos channel inhibitors, as well as drugs targeting other dehydrating cation transporters, may ultimately play an important role in reducing the hemolytic complications of sickle cell disease. However, assessment of the clinical endpoints associated with hemolysis, such as stroke and pulmonary hypertension, is a formidable challenge in clinical trials because such endpoints manifest sporadically or over an extended period of time. But then, the pathway from bench to bedside for any therapy is rarely straight.
Footnotes
Conflict-of-interest disclosure: C.H.J. participated as a site investigator in the phase 3 trial of senicapoc, funded by Icagen (Durham, NC)/McNeil (Fort Washington, PA). He has been a paid consultant for Icagen.
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