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Combination Therapy Exon Skipping for Duchenne Muscular Dystrophy

  • Author(s): Wang, Derek
  • Advisor(s): Miceli, M. C
  • et al.

Duchenne muscular dystrophy is caused by mutations in DMD, resulting in loss of dystrophin essential to muscle health. DMD “exon skipping” uses anti-sense oligo-nucleotides (AON) to force exon exclusion during mRNA processing to restore mRNA reading frame and rescue production of a dystrophin protein with partial functionality. While initial exon skipping drugs in humans show promise, levels of rescued dystrophin protein expression remain suboptimal. Greater benefit is predicted with even modest increases in dystrophin rescue. Using an unbiased screen of FDA approved drugs, we identified dantrolene as a skip-booster when used in combination with AON in human and mouse DMD models. Here, we assess dantrolene booster activity in combination with weekly AON administration in mdx mice over 6 month treatment duration and under conditions that guide pre-clinical evaluation. We find that dantrolene boosts levels of skipped mRNA and rescued dystrophin, resulting in greater reduction of muscle pathology than AON treatment alone and without apparent toxicity. Dantrolene has already been safely administered to a small DMD cohort. Together these findings provide preclinical support for dantrolene/AON combination therapy to increase the efficacy of exon skipping drugs and highlight the value of unbiased screens, combinatorial approaches, and repurposing of FDA approved drugs for discovery of unsuspected therapeutic application and rapid translation.

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