LAUSR

This letter presents some suggestions of possible therapies for sickle cell disease that are based on interpretations of presumed effects of different substrates that alter the cellular levels of ATP. A prevailing idea is that the shrinkage of sickle cells is the result of an increase in intracellular Ca that turns on the Ca-activated K channel (Gardos channel) which causes the cells to shrink and become sickled. The presumption is that the sickled cells can lead to capillary flow blockage resulting in a patient's clinical crisis. If the cellular shrinkage could be prevented the ensuing crisis might be mitigated. The approaches discussed below might be candidates that keep the cells from shrinking. Walter Wilbrandt reported in 1937 that red blood cells exposed to fluoride shrink as a result of the loss of K. This type of K+ loss was later shown to be by the Gardos channel. Importantly, he found that the shrinkage of the cells could be prevented by the addition of pyruvate to the medium. It occurred to me that the effect of pyruvate might be due to the synthesis of ATP by the cell's redox system, which prevented the activity of the Gardos channel. This inhibition could occur by preventing the accumulation of cellular Ca by ATP acting to stimulate the cell's Ca pump. This interpretation has yet to be tested. A second possible approach emanates from a paper from the Agios Pharmaceuticals, Inc., in which they report that their drug, AG-348, significantly increased the intracellular concentration of ATP in normal cells. Obviously, if the idea that the action of pyruvate was via ATP, then the AG-348 drug is a better choice over pyruvate. A third possibility arose with the publication of a clinical trial of testing the effect of glutamine therapy on sickle cell patients. It is thought that the effect of glutamine is to act on the cell's redox system, NAD/NADH. If this is so, then a possible result is that this could increase the cell's ATP concentration by stimulating glycolysis. This could mimic the effect of pyruvate considered above. It is obvious that the underlying suggestion in all of the above approaches relies on the central role of cellular ATP. It seems straight forward that these effects are easily testable on sickle cells as a function of aerobic/anaerobic conditions. Perhaps these types of results will be soon forthcoming. CONFLICT OF INTEREST The author declare that they have no financial conflicts or conflicts of interest with the contents of this article.