Desmin cardiac myopathy: molecular pathogenesis and novel treatment concepts

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Heterozygous and homozygous mutations of the human desmin gene cause familial and sporadic cardiomyopathies and myopathies. Cardiac involvement frequently leads to progressive heart failure or sudden cardiac death. In our previous work we have characterized the clinical, myopathological, and molecular consequences of a human R350P desmin missense mutation, which is the most frequently encountered gene defect causing desminopathies in Germany.We have successfully generated heterozygous and homozygous R350P desmin knock-in mice. First analyses of these animals revealed histopathological, in vivo electrophysiological and functional characteristics of the human desmin cardiomyopathy. In addition to a more detailed pathophysiological analysis of our R350P desmin knock-in mice, we will further study the pathological impact of two further domain-specific human desmin mutants (R16C, head domain; K449T, tail domain) using cardiac gene transfer with adeno-associated virus (AAV) vectors. Since no specific therapy is available for human desminopathies, we will evaluate the therapeutic potential of novel therapeutic approaches. In a first step, we will test the hypothesis if the AAV-mediated over-expression of small heat shock proteins (αBcrystallin, Hsp70) exert a cardio-protective effect in our desminopathy mouse models. In a second step, we will address the cell protective effect of heat shock protein inducing drugs (geranylgeranylacetone, paeoniflorin) on cardiomyocytes from these mouse models. Our work shall provide deeper insights into the molecular pathogenesis of desmin cardiomyopathies and evaluate the basis for novel treatment concepts.