A mitochondrial therapy for muscular dystrophies

Mitochondria are our energy factories, organelles where cellular respiration takes place and most ATP – the energy currency of the cell – is produced. Mitochondria also possess a channel (the permeability transition pore, PTP) whose excessive opening can cause an energetic short circuit with energy dissipation, decreased muscle contractility and early death of fibers. The PTP is activated by oxidative stress and calcium overload, two key factors that can lead to the early demise of muscle fibers. We have developed novel triazole inhibitors of high potency that proved very effective at curing Zebrafish affected by collagen (col) VI myopathy and by the equivalent of Duchenne muscular dystrophy (DMD). These compounds also allowed recovery of the otherwise defective respiration of muscle fibers from patients. Here we will assess pharmacokinetics and efficacy of novel triazole-based PTP inhibitors in two mouse disease models: (i) the Col6a1^-/- mouse lacking colVI, a model of Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy; and (ii) the mdx^5Cv mouse lacking dystrophin, a model of DMD. Potential liabilities will be assessed through a panel of established in vitro assays for off-target effects. This program could provide a completely new way to treat muscular dystrophies and stimulate the testing and application of the “mitochondrial therapy” to other diseases where mitochondria are part of the pathogenic cascade. Importantly, our treatment could be used in combination with drugs or genetic tools that act on different steps in disease onset and progression, a combinatorial approach that could be key to therapeutic success.