A mitochondrial therapy for muscular dystrophies

Muscular dystrophies are genetic, progressive diseases for which no effective therapies are available. We have discovered why muscle fibers degenerate in human muscular dystrophies caused by abnormalities of collagen VI, i.e. Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). The absence of collagen VI has a major impact inside the fibers by triggering a short circuit in the cell's energy generators, the mitochondria. This short circuit is caused by opening of a channel called the "Permeability Transition Pore" (PTP), which can be inhibited by cyclosporin A (CsA). We have been able to block the short circuit and to cure the disease in a mouse lacking collagen VI; and we have shown that cells from patients affected by UCMD and BM also respond to CsA. A short-term pilot trial with CsA in patients affected by UCMD and BM has provided encouraging results, but long-term use of CsA may expose the patients to the risks of immunosuppression. To overcome this hurdle we have (i) successfully tested NIM811 (a derivative of CsA that inhibits the PTP but does not cause immunosuppression, and showed superior efficacy compared to CsA); (ii) shown that pargyline (an inhibitor of monoamine oxidases that acts upstream of the PTP to reduce oxidative stress) is effective in cells from patients; and (iii) developed novel drugs acting on the PTP that display synergistic effects with CsA in vitro (i.e. the effects of the drugs given together with CsA are larger than the sum of the effects of CsA and of the drugs used individually). We will study the efficacy of a "combinatorial" therapy of human collagen VI and Duchenne muscular dystrophies in animal models and patients’ cells in order to define a therapy for the patients.