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LAMININ AS A THERAPEUTIC TARGET FOR MUSCULAR DYSTROPHY
AdvisorBurkin, Dean J.
Cell and Molecular Pharmacology and Physiology
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Muscular dystrophies (MD) are a group of devastating diseases that result in increasing degeneration of skeletal muscle. Two of the most common MDs are Duchenne muscular dystrophy (DMD) and LAMA2-related Congenital Muscular Dystrophy (LAMA2-CMD). DMD is caused by mutations in the gene that encodes for dystrophin and LAMA2-CMD is caused by mutations in the gene that encodes for laminin-α2. Both mutations result in structural disruption of muscle fibers resulting in constituent degeneration, fibrosis and immune cell infiltration. However, both MDs have distinct disease mechanisms and pathogenesis. Laminin-111 is a disease modifier for both DMD and LAMA2-CMD. Exogenous treatment with Laminin-111 in different mouse models of DMD and LAMA2-CMD has demonstrated improvement in muscle pathology by increasing regeneration, repair and muscle strength. In this project, we show that intramuscular treatment with Laminin-111 improves regeneration and in vivo muscle contractility in the Golden Retriever Muscular Dystrophy (GRMD) dog model of DMD. We also show that systemic treatment with Laminin-111 is able to prevent contraction-induced damage in an older mouse model of LAMA2-CMD. Additionally, we tested the human isoform of Laminin-111 and Laminin-211 in a novel immunocompromised mouse model of LAMA2-CMD, where we show increased regeneration and differential effects in the cellular differentiation of muscle stem cells in vivo. Together these results show that Laminin-111 protein therapy appears to be therapeutic across two muscular dystrophies despite the differences in pathology.