RESTORING CELL-EXTRACELLULAR MATRIX INTERACTIONS TO RESCUE TISSUE DEGENERATION AND FAVOR REPAIR IN HEREDITARY NEUROPATHIES

Progressive tissue degeneration and defective regeneration are major hallmark for hereditary neuropathies (HN) and congenital muscular dystrophy (CMD), which results in motor and sensory deficits that cause disability. Although clinical manifestations are well described and many genetic causes identified, much remains unknown regarding their pathogenesis and no efficient therapy is available. Tissue degeneration and defective repair in HN and CMD may be the consequence of the abnormal relationship between the resident cells and the surrounding extracellular matrix (ECM). When the ECM composition and structure is altered, for example due to genetic defects as in LAMA2 disorder (one of the CMD) or for excessive accumulation of ECM component such as fibrin and vitronectin, neuromuscular tissue undergoes degeneration and repair is impaired. In this grant application we plan to better elucidate the pathological mechanisms that cause progressive neuromuscular degeneration and defective repair, and to attempt rescue approaches for both HN and CMD in animal models. In AIM1 we will extend our study on the ECM composition in HN, and will evaluate if increased fibrinolysis in animal models of HN would ameliorate neuropathy and repair. In AIM2 we will explore if defective ECM polymerization in LAMA2 models may be rescued by mesoangioblast cell delivery of a mini-agrin protein that can cross-bridge orphan laminin2 receptors with other laminin chains upregulated in these mutants. We expect to rescue degenerative disorders and favor repair processes by the manipulation of the ECM composition.