Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the dystrophin gene that leads to absence of dystrophin expression in muscles. Many of the mutations that cause DMD are so-called nonsense mutations. They are generally caused by single point mutations in the dystrophin gene that lead to the inappropriate presence of premature stop codons (UAA, UAG or UGA) causing a premature arrest in the synthesis of the dystrophin protein. Preclinical studies in our laboratory demonstrate that systemic administration of compound RTC13, an experimental drug that has been recently identified, restores body wide dystrophin expression in mdx mice, a widely used animal model of DMD. Muscle function was also significantly improved. Our goal is to determine whether this compound is safe to use in patients and to optimize the dose necessary to achieve therapeutic effects in DMD boys. It has been estimated that approximately 13% of DMD patients could benefit from read through of nonsense mutations. Two major components will be covered by this proposal. First, using in vitro and in vivo models we will optimize the chemical structure of RTC13 necessary to achieve maximal absorption into muscle after oral administration while still maintaining optimal efficacy and safety profiles (Aim 1). Dose response studies will then be performed in the mdx mouse to determine the clinical beneficial effects achieved after oral administration of RTC13 (Aim 2). The efficacy of the compounds tested will be explored using a combination of approaches aimed at measuring protein function, muscle physiology and improvement in muscle pathology. If RTC13 can be successfully used to restore dystrophin production with resulting clinical benefit, we will begin planning for the clinical trials in human.
Approximately 30% of the mutations causing human genetic disorders are nonsense mutations. To date, there are no efficient treatments for the majority of these genetic disorders. The development of a drug that can read- through premature termination codons will have a wide range of application in treating these disorders. The proposed study will enable us to determine the safety, tolerability and efficacy of an orally viabl nonaminoglycoside read-through drug that can then be tested in human clinical trials.
|Bertoni, Carmen (2013) Therapy development for neuromuscular diseases: translating hope into promise. Future Neurol 8:|