Prof. Michael Sinnreich, University of Basel, Dept. Neurologie & Biomedizin

Abstract

No treatment is currently available for patients with muscular dystrophies. Finding therapies is imperative as these disabling neuromuscular diseases have a high personal and socioeconomic impact. Dysferlin is a transmembrane protein implicated in surface membrane repair of muscle cells. Mutations in dysferlin lead to progressive muscle membrane damage and cause the muscular dystrophy Miyoshi Myopathy, Limb Girdle muscular Dystrophy Type 2B and Distal Anterior Compartment Myopathy.
In this application we propose to test the following therapeutic approaches for dysferlinopathies:

(i) From recently perfomed in-vitro experiments we have a strong indication that inhibition of the degradation pathway of mis-sense mutated dysferlin could be used as a therapeuric strategy for patients with specific dysferlin mis-sense mutations (Azakir et al. 2012a). In this application, we propose to generate a knock-in mouse model of dysferlinopathies harbouring a mis-sense mutation and to investigate the effect of the inhibition of the degradation pathway of mis-sense mutated dysferlin on muscle histology and function of the generated knock-in mice.

(ii) We propose to test AAV (Adeno Associated Virus) mediated gene transfer in mouse models of dysferlinopathies using recombinantly generated mini-dysferlin molecules capable of reparing laser induced plasmalemmal wounds in cultured dysferlin deficient human myoblasts (Azakir et al. 2012b).

(iii) We have observed taht a small protein, synaptotagmin VII, containing homologous C2 domains to dysferlin, can restore plasma membrane defects in dysferlin deficient myoblasts. We propose to generate a transgenic mouse models overexpressing synaptotagmin VII and crossing it with dysferlin deficient mice to detremine whether synaptotagmin VII can rescue the membrane repair defect and reverse the myopatthology observed in dysferlin deficient mice.

The proposed translational experiments aim at developing novel treatments for patients with muscular dystrophy due to dysferlin deficiency and have a very high clinical relevance.