New therapeutic approaches to sickle cell disease Volume 12, issue 4, Juillet-Août 2006


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Department of Laboratory Medicine and Pathology, Children’s Hospital, Harvard Medical School, Boston, MA, USA, Department of Clinical and Experimental Medicine, Section of Internal Medicine, University of Verona, Italy

Following the generation of transgenic mouse models of sickle cell disease, pre-clinical trials have shown the beneficial effects of various potential therapeutic molecules for the acute or chronic manifestations of the disease. Several molecules are upon evaluation in phase I to phase III clinical trials. These therapeutic approaches target: 1) membrane cation transport systems and channels involved in sickle cell dehydration; 2) adherence of erythrocytes to endothelium; 3) activation of circulating and endothelial cells participating in the vaso-occlusive events and local ischemia. The Gardos channel (calcium activated potassium channel KCNN4) is inhibited by the clotrimazole metabolite ICA-17043, in phase III trial. The K-Cl co-transport (KCC1/3/4) activated by the depletion of erythrocyte magnesium is inhibited by Magnesium pidolate; dipyridamole inhibits ion transports upon deoxygenation. Sulfasalazyne (inhibitor of the NF-κB pathway) inhibits the anormal activation of endothelial cells. Nitric oxide (NO) is the most potent vasodilator. It prevents the activation of leucocytes, platelets and endothelial cells in patients with sickle cell disease and vascular remodelling. The L-arginine, the NO precursor, provides could be beneficial in sickle cell patients.