An in vivo model of intractable R257C-ACTG2 Visceral Myopathy to study pathogenesis and to identify new disease targets

Visceral myopathies (VSCM) are a group of rare genetic diseases impairing both oral nutrition and development in affected individuals. Forms of VSCM characterized by lack of visceral muscle contraction often result in chronic intestinal pseudo-obstruction (CIPO), a life-threatening medical emergency requiring immediate medical attention. To date, resolutive therapies are lacking and patients often require nutrient delivery in the bloodstream for life or even intestinal transplantation. Our project aims at providing highly innovative tools to study one of the most common and intractable forms of pediatric CIPO due to a R257C mutation in the actin gamma2 gene (ACTG2). Thus, we have established a genetic model using the fruit fly Drosophila melanogaster that mimics CIPO and will inform us on its disease development. We propose to use such an in vivo model to first explore fly gut structure, contractility and ability to allow food transit. We will also study the little explored cellular aspects of myopathy focusing on actin function and autophagy activity. Finally, we will identify candidate genes that might be important for the disease and select potential existing drugs that might ameliorate defects in contractility. Validation of initial hits will be performed by collaborators that will assess activity on edited human smooth muscle cells. By exploiting an experimental platform that mimics the physiological and pathological characteristics of the intestinal muscle tissue, our project represents an original approach, which we hope will make inroads toward knowledge-based novel treatments for a neglected syndrome.