Résumé :
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Background: Mutations in LAMA2, the gene encoding the laminin-alpha2 chain of the extracellular matrix of muscle cells, cause a rare and severe form of congenital muscular dystrophy, called MDC1A. The disease is characterized by early onset, progressive muscle degeneration and impaired regeneration. As consequence, affected children are often never able to walk and, as there is no effective treatment available, frequently die in early childhood. Genetic evidence has shown that overexpression of the apoptosis inhibitor protein BCL-2 can protect from disease-relevant pathologies in the laminin-alpha2 deficient dyW/dyW mouse, a model for MDC1A. In addition, expression of a miniaturized form of the extracellular matrix molecule agrin (mini-agrin) has been shown to be an alternative way to ameliorate disease symptoms. Methods: The efficacy of omigapil (N-(dibenz(b,f)oxepin-10-ylmethyl)-N-methyl-N-prop-2-ynylamine maleate; SNT-317, TCH-346), a chemical derivative of selegiline, was tested in dyW/dyW mice by oral administration at a daily dose of 0.1 or 1 mg/kg starting at 3-weeks of age. Control animals were treated with vehicle. Results: We show that omigapil, a well characterized inhibitor of apoptosis that targets GAPDH, ameliorated key pathology hallmarks of the dyW/dyW mouse. Specifically, oral administration of omigapil reduced apoptosis in muscle and preserved muscle histology, reduced body weight loss, mitigated skeletal deformation and improved locomotion. Moreover, omigapil increased the 50% survival time from ~35 days in vehicle treated dyW/dyW mice to ~85 days and ~105 days in dyW/dyW mice treated with 0.1 mg/kg and 1 mg/kg omigapil, respectively. In addition, we show that co-administration of mini-agrin had additive beneficial effects. Discussion: The preclinical and clinical development of omigapil is well advanced and omigapil was proven to be safe in large clinical trials. Based on its efficacy in the dyW/dyW mouse, this orally bioavailable drug is well suited to be tested clinically as a potential therapy for MDC1A.
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