Effect Of Nutrients On Duchenne Muscular Dystrophy Mice

Duchenne Muscular Dystrophy is a recessive X chromosome linked neuromuscular disorder.Frame-disrupting mutations in human DMD gene leads to the deficiency of functional dystrophin protein,resulting in muscle membrane leakage.Due to the leaky muscle membrane,muscle fibres enter into the cycle of degeneration and regeneration upon injury and DMD patients gradually lose muscles and eventually succumb to respiratory failure.Most of DMD patients can not live beyond their early 30 s.Currently there is no effective treatment available for DMD patients.Although the first-ever antisense oligonucleotide drug(eteplirsen in the PMO backbone)was approved by the US FDA,its low systemic efficacy,high doses required and related intimidating cost remain hurdles to overcome.To address this,we started to screen small compounds in mdx mice intramuscularly and wished to identify some effective compounds to enhance the activities of PMO and to improve pathological conditions in mdx mice.Based on previous local screening results,we found that three nutrients namely A1,A2 and A3 showed the potential.Therefore,in the current study,we systemically evaluate A1-A3 in mdx mice for their potential to improve the activities of PMO and the pathological conditions in mdx mice.The results demonstrated that A1 failed to enhance the activity of PMO after 3 weekly intravenous injections of PMO in A1 at the dose of 25mg/kg.Importantly,both A2 and A3 promoted the activity of PMO and improved the pathological conditions in mdx mice under identical conditions.Strikingly,more frequent administration of A2 or A3 could further enhance the effect.Based on these observations,we administered A3 alone in mdx mice intravenously three times per week for 3 weeks or 3 months.The results showed that A3 alone could improve the pathological conditions and muscle force and endurance of mdx mice without any detectable adverse effect.In summary,our study demonstrates that A2 and A3 can promote the activity of PMO and induce higher level of dystrophin protein expression,resulting in improved phenotypic rescue and functional improvement.A3 alone can also improve the pathological conditions and functions of mdx mice without any detectable toxicity.Our study provides a new adjuvant for antisense oligonucleotide-mediated exon-skipping therapeutics in DMD.