Melusin gene therapy: a possible approach to prevent cardiomyopathy

Cardiomyopathies are life threatening diseases caused in large part by hereditary genetic mutations leading to progressively impaired heart function. Since these pathologies are generated by several possible gene mutations, conventional gene therapy targeting each specific mutation is not always feasible. Mutation-independent gene therapy approaches could be greatly advantageous being, in principle, applicable to cardiomyopathies generated by different, as well as not yet identified, mutations. Here we plan to test the efficacy of a gene therapy approach based on overexpression of melusin gene coding for a muscle-specific protein with chaperone activity. Chaperones are naturally occurring proteins that recognize a broad panel of proteins partially damaged by stress conditions or genetic mutations allowing them to retain correct function. We have previously demonstrated that melusin is present in muscles and heart and it is required for the heart response to stress stimuli such as aortic stenosis. Moreover, melusin overexpression effectively counteracts cardiomyopathy induced by aortic stenosis and myocardial infarct. Here we propose to use melusin gene therapy as mutation-independent approach to buffer the cellular stress induced by genetic mutations in mouse models of familial cardiomyopathy.