Résumé :
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Congenital Muscular Dystrophy (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. The most frequent form is due to mutations of the LAMA2 gene encoding the laminin alpha2 chain, which forms merosin the predominant laminin isoform of muscle and nerve basement membrane. Although much is known about clinical aspects and genetic causes of CMD, and about the pathological mechanisms that lead to muscle and nerve degeneration, no useful therapy to arrest neuromuscular degeneration and to promote tissue repair is available to date. As a proof of principle the overexpression of laminin2 or mini-agrin, a cross-linker molecule that allows reconnection of the basement membrane to the resident cells, showed amelioration of CMD in animal models. However, at present direct viral transduction of exogenous proteins into human tissues is not feasible. Cell therapy may instead constitute a promising tool to speed translation into clinical practice. Mesoangioblasts have shown promising results in terms of amelioration of muscular dystrophy phenotype and reconstitution of missing proteins in pre-clinical experiments. We infected mesoangioblasts with lentivirus vectors carrying a mouse mini-agrin gene. Mesoangioblasts can synthesize and deliver mini-agrin in vitro and in vivo. We injected the engineered mesoangioblasts in the vein tail of CMD model, dy2J/dy2J mice. Mesoangioblasts carrying the mini-agrin gene were able to fuse into myotubes of dy2J mice, many of these myotubes expressed the mini-agrin protein, and these mice displayed amelioration of muscle histology and clinical phenotype.
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