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Projekt Druckansicht

Desmin cardiac myopathy: molecular pathogenesis and novel treatment concepts

Fachliche Zuordnung Molekulare und zelluläre Neurologie und Neuropathologie
Förderung Förderung von 2012 bis 2017
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 101925924
 
Erstellungsjahr 2017

Zusammenfassung der Projektergebnisse

Mutations of the human desmin gene on chromosome 2q35 cause autosomal-dominant and -recessive myopathies and cardiomyopathies. To date no curative therapy is available for this progressive and often lethal disorder. In the current project we addressed the molecular pathophysiology of the disease and performed a preclinical evaluation of AAV9-mediated gene therapy approaches for the cardiomyopathy in recessive desminopathies. A first major contribution of our project work was the successful generation and characterization of hetero- and homozygous R349P desmin knock-in mice, which serve as real patient-mimicking mouse models for both the autosomal-dominant and the autosomal-recessive human desminopathies with maintained desmin protein expression, respectively. Both, hetero- and homozygous R349P knock-in mice develop cardiomyopathy as well as increased susceptibility for cardiac arrhythmias and conduction defects. In extension to our initial workplan, we put an additional work focus on the analysis of the cardiac pathology in desmin knock-out mice (model for autosomal-recessive human desminopathies with lack of desmin protein) and in mdx mice (model for X-linked Duchenne muscular dystrophy and cardiomyopathy) as well as the skeletal muscle pathology in human desminopathies and our R349P desmin knock-in mice. The desmin knock-out mice were primarily used for our first AAV9-mediated desmin gene transfer experiments. A dose of 3x10^12 AAV9-wild-type desmin vector genomes led to a partial reconstitution of wild-type desmin protein expression, which was accompanied by reduced cardiac fibrosis and improved systolic left-ventricular function. Notably, a higher dose of 5x10^12 AAV9-wild-type desmin vector genomes resulted in a full desmin reconstitution in the heart in combination with a nearly complete normalization of the key morphological and functional cardiac parameters. Thus, the highdose AAV9-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression. However, the highdose AAV9-mediated reconstitution of wild-type desmin expression in the hearts of our homozygous R349P desmin knock-in mice did not improve the morphological and functional cardiac parameters but instead showed a tendency to worsen the outcome parameters. Furthermore, we could demonstrate that the AAV9-mediated overexpression of αB-crystallin resulted in a significant improvement of hemodynamic cardiac parameters in treated mdx mice. In contrast, our AAV9-mediated gene transfer of the R16C desmin head and the K449T tail domain mutations into adult wild-type mice apparently did not yield in a high enough expression level to cause disease-specific morphometric, histological and echocardiographic pathologies. Our studies on the skeletal muscle pathology further demonstrated that the expression of mutant desmin causes a multi-level pathology, which primarily affects the extrasarcomeric desmin intermediate filament cytoskeleton and subsequently leads to disturbances of the alignment and orientation of myofibrils, the localization, morphology and function of mitochondria, the structural integrity of neuromuscular junctions as well as the biomechanical stress resistance of muscle fibers. Taken together, our project provided substantial new insights into the molecular pathophysiology of desminrelated cardiomyopathies and myopathies and, moreover, paved the way towards novel gene therapy approaches for the treatment of autosomal-recessive desminopathies with a lack of desmin protein expression.

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