Abstract:
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CMD is characterized by progressive wasting muscular dystrophy and dysmyelinating neuropathy with variable involvement of the central nervous system, which may lead to severe disability in early childhood. Among this group, laminin 2deficient CMD (MDC1A) is the most severe form. This is due to mutations of the LAMA2 gene encoding the laminin alpha2 chain, which forms laminin2 the predominant laminin isoform of muscle and nerve basement membrane. So far, there is no curative treatment of MDC1A. Recent studies have shown that cell therapy with mesoangioblasts, a class of vessel-associated stem cells, which can differentiate in mesoderm cells including myocytes, are able to restore defective protein levels and motor skills in animal models of muscular dystrophy. Morever the overexpression of a miniaturized form of agrin (mini-agrin), a laminin/laminin-receptor crosslinker molecule, was shown to markedly lower muscle degeneration and decelerates disease progression in mouse models for MCD1A. In our study, mesoangioblasts were infected with a lentiviral vector carrying a mouse mini-agrin gene and injected in a MDC1A model. Immunohistochemistry has demonstrated that mesoangioblasts expressing the mini-agrin protein fuse with the resident muscle fibers in the injected mutant mice. Also these mice showed an improvement of muscle histology and an increased amount of laminin-receptors at the muscle cell surface. Finally, these mice had better performance with treadmill assay with respect to non-injected mice.
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