Hereditary chloride channelopathies of skeletal muscle and kidney: From genotype to phenotype and novel pharmacotherapeutical approaches

This project is focused on the identification of drugs for the treatment of patients suffering from genetic ion channelopathies, for which gene therapy is far to be achieved, including Myotonia Congenita (MC) affecting skeletal muscles, Bartter syndrome and salt-sensitive hypertension affecting kidneys. These disorders are linked to mutations/polymorphisms in the genes encoding chloride channels of the CLC family, which play a crucial role in controlling skeletal muscle excitability and renal salt reabsorption. The pharmacotherapy of these diseases is actually purely symptomatic, with obvious efficacy and toxicity pitfalls. Our effort is thus committed to find safe therapy by identifying drugs to treat individual patients with high specificity and efficiency. This is a revised application of a new project proposed by a former granted applicant, who has long been interested in searching for better pharmacological approaches in ion channelopathies. Here, we will characterize novel ClC channel mutations to correlate the biophysical defect with the clinical phenotype in MC. We plan to elucidate the mechanism of action of acetazolamide on ClC channels, which has been used empirically in myotonic syndromes. Recently, we have found a series of molecules able to modulate renal CLC channel function, which may offer the possibility to develop new pharmacotherapeutic approaches with greater efficacy and reduced toxicity. Our strategy includes biophysical tests of these molecules on wild-type and mutated chloride channels in conjunction with drug modeling rational design, and in vivo studies on spontaneously hypertensive rats. At the end, the understanding of the genotype/phenotype relationship of chloride channelopathies would help physicians in establishing an accurate diagnosis and deciding the best medication, while strong scientific information and pre-clinical drug screening would open the way for warranted clinical trials.