PHARMACOLOGICAL EVALUATION OF PROMPT-TO-USE DRUGS SELECTIVELY TARGETING SODIUM AND POTASSIUM CHANNELS OF EXCITABLE TISSUES FOR THERAPEUTIC USE IN SKELETAL MUSCLE, HEART, AND BRAIN CHANNELOPATHIES

This project deals with heritable ion channelopathies characterized by abnormal excitability of the skeletal muscle, heart, and brain, which include periodic paralysis, myotonic syndromes, life-threatening cardiac arrhythmias, and some forms of epilepsy. These disorders are linked to mutations in the genes encoding ion channels, especially voltage-gated sodium and potassium channels, which play a crucial role in controlling the excitability of skeletal muscle, heart, and brain. The current pharmacological therapy is empiric, based in part on the use of carbonic anhydrase inhibitors in several of these diseases or sodium channel blockers in others.In previous projects granted by Telethon, we demonstrated that CA inhibitors act in periodic paralysis by opening a subtype of potassium channels, named BK channels, and we defined the molecular mechanisms that govern the specificity of sodium channel blockers in myotonic syndromes.On the basis of these results, we wish to extend our study to other drugs, already available on the market, as well as other excitability diseases including those affecting the heart and brain. Our effort is therefore devoted to find safe therapy by identifying drugs prompt-to-use in the clinic to treat individual patients with high specificity and efficiency. Our strategy is based on biophysical tests of drugs with known pharmacological/toxicological profiles on the various BK and sodium channels expressed specifically in the excitable tissues in conjunction with the virtual screening of databases to identify drugs with favorable toxicological profiles. We expect that this approach would speed up the time of finding new drugs useful in these disorders for which an efficient gene therapy is far to be achieved.