Purpose. Familial cardiomyopathies are caused by genetic mutations that induce accumulation of misfolded proteins with consequent cardiomyocyte death and maladaptive cardiac remodelling. Molecular chaperones are a family of proteins devoted to prevent accumulation of misfolded proteins by promoting either their refolding or degradation via the ubiquitin-proteasome or the autophagosome systems and can thus represent a potential mean to treat familial cardiomyopathies.
Methods. Melusin is a muscle specific chaperone protein whose overexpression effectively prevents maladaptive cardiac remodeling and heart failure both in pressure overload and myocardial infarct mouse models. In this study we use in vivo gene delivery with cardiotropic adeno associated virus 9 vector to induce to increase melusin expression in the heart of mice carrying H222P Lamin A mutation mimicking human Emery-Dreifuss familial cardiomyopathy. Mutant male mice develop spontaneous dilated cardiomyopathy from 4 months of age and die within 10-12 months of age.
Results. Homozygous mutant mice were injected with AAV9-Melusin (I.V. injection of 1012 viral particles/mouse) either at 1 month of age before development of the cardiomyopathy or at 4 months when cardiomyopathy was already present to test for both preventive and therapeutic activity. Cardiac function was monitored by echocardiography for the following months. While untreated mice progressively developed left ventricle dilation and reduced contractility (FS%), mice injected with AAV9-Melusin retained physiological level of contractility and were protected toward LV dilation. Ten months after the treatment, 40% of mutant mice died, while 100% of melusin-treated mice were alive. A second group of mutant male mice was injected with AAV9-melusin at 4 months of age when the cardiomyopathy was already detectable. Interestingly melusin prevented the deterioration of contractility in the following 6 months and significantly reduced mortality.
Conclusions These data indicate that melusin chaperone overexpression can effectively delay the onset of Emery-Dreifuss cardiomyopathy as well as arrest the progression of the already established pathology.