G.P.120

Abnormal intracellular calcium load is one of the most consistent findings in Duchenne muscular dystrophy (DMD) but previous attempts to improve the dystrophic pathology with calcium antagonists have been unsuccessful. However, there is an intriguing possibility of restoring calcium homeostasis indirectly by exploiting the relationship between the Sodium/Hydrogen Exchanger (NHE-1) and the Sodium/Calcium Exchanger (NCX). NHE-1 has been reported to be abnormally overactive in DMD models, leading to an increased influx of sodium which in turn switches the NCX into reserve mode leading to calcium influx. Using selective NHE-1 inhibitors the influx of sodium can be reduced thereby allowing the NCX to revert back to normal mode, where calcium is extruded, thus reducing the cellular calcium load. In collaboration with our industrial partner Peacock Pharma, we have demonstrated the potential of NHE-1 inhibition in the mdx mouse model for DMD by chronically treating animals with a novel NHE-1 inhibitor. The pilot study showed significantly reduced calcium uptake in treated mice ( n  = 6) using manganese enhanced MRI (MEMRI). Manganese acts as a contrast agent in T1 weighted MRI and is thought to be taken up by cardiac and skeletal muscle by the same receptors as calcium. There was also an increase in functional grip strength, although not statistically significant the results are nevertheless encouraging and indicate the potential of this novel approach in DMD. This is currently being investigated more thoroughly using a greater number of animals ( n  = 12) treated chronically via drug in chow over 6-months and assessed using MEMRI and grip test. In addition, in vitro calcium-flux assays (e.g. Fluo-4) are used to determine the potency and investigate the mechanism of action of this drug. The objective of our study is to provide the requisite pre-clinical data that would enable these drugs to progress towards clinical trials.