Preclinical evaluation of pharmacogenetics and new therapeutic options in nondystrophic myotonias toward personalized medicine

The project focuses on the identification of new therapeutic options for patients suffering from nondystrophic myotonias, a group of skeletal muscle genetic diseases caused by mutations in muscle ion channels, which are membrane proteins involved in chloride or sodium ion transport. These rare diseases (prevalence of about 1/100,000 in Europe, yet more than 500 diagnosed in Italy) are largely neglected by public and private investors. The mutations causing myotonia increase the excitability of skeletal muscle, leading to muscle stiffness after contraction. Myotonia can be chronically debilitating due to pain and muscle stiffness, which are associated with frequent falls and disability. Gene therapy for these diseases is very far to be achieved. The available therapy presents significant efficacy/toxicity pitfalls. The preferred antimyotonic drug is the sodium channel blocker mexiletine. However, many myotonic patients do not gain benefit from mexiletine, because the drug is unavailable in some countries, is contraindicated in cardiomyopathic individuals, induces limiting side effects, or produces suboptimal or non response. We propose to test a number of drug candidates in cell lines expressing sodium channel mutants and in a rat model of myotonia. The examined sodium channel mutations and drug candidates will be chosen in collaboration with neurologists and the Italian parents association MiA ("Miotonici in Associazione"), on the basis of clinical experience and our knowledge of the relationship between mutations and ion channel function. These pharmacological studies performed in in vitro and in vivo models would allow to discover new promising antimyotonic drugs and to define a pharmacogenetic strategy, that is to define the best drug on the basis of the specific mutation carried by each individual. These expected preclinical results will offer a solid scientific basis for future warranted clinical trials.