Résumé :
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A potential strategy to treat Duchenne muscular dystrophy (DMD) is to compensate the absence of dystrophin by up-regulation of the homologous protein, utrophin. An approach to up-regulate utrophin expression and improve dystrophic phenotype in dystrophin-deficient mdx mice is through the stimulation of the nitric oxide (NO) pathway. Interestingly, the group of Perrine & Faller renews the expression of fetal hemoglobin by the administration of arginine butyrate (AB), in order to treat the beta-globin disorders (sickle-cell disease and beta thalassemia). Butyrate's effect is hypothesized to occur by the inhibition of histone deacetylases (HDAC) enzymes. Several studies suggest that the drug is safe for pediatric patients. These data made us think of AB as a potential therapeutic candidate for renewing utrophin, which can be considered as a fetal homologue of dystrophin. In the present study, we investigated the effects of AB, which combines two key pharmacological activities, i.e., NO pathway activation (arginine) and HDAC inhibitor (butyrate). A previous work initiated by Domain Therapeutics, a private company, was performed with high dose of BA for a long period (6 months) demonstrated that BA produced only modest beneficial effects in mdx mice but with a good tolerance of the product, compared to prednisone (an immunosuppressor). Here we show that continuous i.p. administration of arginine butyrate to dystrophin-deficient mdx mice increased utrophin expression in skeletal muscle, heart, and brain and improved the dystrophic phenotype, both in adult and newborn mice. We also used intermittent administration on mdx mice. The treatment was efficient on utrophin expression and dystrophic phenotype, with the advantage to reduce the frequency of injections and to improve the tolerance. A single serie of 4 injections was sufficient to enhance the expression of utrophin, embryonic myosin and beta-dystroglycan in muscle tissues. Biopsies could thus be performed shortly after the beginning of the treatment and used as a biochemical marker of treatment efficacy. We further show that skin biopsies can be used to monitor the assay, in place of invasive muscles biopsies. Finally, arginine butyrate also increased utrophin expression in cultured human myotubes. All together we consider that these data constitute the proof-of-principle of the benefit and good tolerance of the product, and that move toward an application to treat DMD patients appears justified.
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