Extraocular muscle stem cells for DMD therapy

University Of Pennsylvania, Philadelphia PA

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Abstract

Duchenne's muscular dystrophy (DMD) is a fatal disorder caused by mutations in the DMD gene that results in an absence or severe reduction of dystrophin. Current therapies can not significantly slow down, let alone cure the disease. Our proposal stems from the basic observation that EOMs remain clinically and pathologically spared even in advanced cases of DMD. This presents an intriguing conundrum since we have previously shown that normal human EOM produce full-length dystrophin and that dystrophin is completely absent in the EOM of DMD patients. This phenomena extends across species as EOM are spared in the canine (GRMD) and murine (mdx) models of DMD. No satisfactory explanation for EOM sparing exists, despite many hypotheses having been proposed and tested. Three key findings suggest a novel hypothesis related to EOM stem cells to explain EOM sparing in DMD. First, adult muscle has been shown to contain stem cells that are capable of diving, transdifferentiation and engraftment. Second, expression profiling and metabolic labeling experiments suggest that the continual myogenesis seen in adult EOM may be related to increased numbers of stem cells resident in EOM. Third, the mdx phenotype has been shown to be ameliorated by myostatin blockade-mediated enhancement of myogenesis/regeneration. We propose to test the hypothesis that EOM stem cells contribute to sparing of EOM in DMD. We will test this hypothesis by analyzing a) the number and b) the engraftment and therapeutic potential of stem cells resident in adult EOM compared to limb muscle in a series of in vitro and in vivo experiments. The studies are critical for advancing our basic understanding of DMD pathophysiology. Additionally, undertaking this research would provide a proof-of-principle for a strategy designed to harness the myogenic md stem cell potential of adult EOM as a possible means of DMD-therapy.