Modulation of the cyclin inhibitor p27 to ameliorate Merosin Deficient Congenital Muscular Dystrophy (MDC1A)

Merosin Deficient-Congenital Muscular Dystrophy 1A (MDC1A) is an autosomal recessive disorder due to mutations in the LAMA2 gene, which encodes for the laminin2 protein. The disease is characterized by progressive-wasting muscular dystrophy, peripheral neuropathy, and brain abnormalities. As a consequence, muscles and nerves devoid of laminin2, progressively degenerate causing muscle weakness, hypotonia and contractures, which manifests from the first decade of life. No therapy is available until now. We recently identified in Lama2 mouse models a new pathogenetic mechanism involved in this disorder. Our findings suggest that tissue degeneration may be due to dysregulated levels of Jab1 and p27, two proteins that control cell cycle progression and differentiation. Our preliminary findings suggest that regulation of p27 levels may ameliorate the disease. The main goal of this project is to assess whether genetic and pharmacological modulation of p27 represents an effective strategy to ameliorate MDC1A. We will evaluate consequence of p27 modulation on nerve and muscle regeneration. This information will be collected in rodent and human cells in vitro, and mouse models of the disease in vivo. With this project we aim at generating proof of principle data to set up potential effective treatments for MDC1A disease.