Toward a mitochondrial therapy of collagen VI muscular dystrophies (TELETHON GRANT GGPO8107)

Muscular dystrophies are genetic, progressive diseases for which no therapy is currently available. We have discovered why muscle fibers degenerate in two human muscular dystrophies caused by abnormalities of Collagen VI, 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 the drug cyclosporin A (CsA). We have blocked the short circuit and cured 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 will test the efficacy of a derivative of CsA that inhibits the PTP but does not cause immunosuppression, and which we have already shown to be effective in curing the patients’ cells in vitro. We will also identify further potential targets for pharmacological intervention, with the goal of providing an effective treatment for human Collagen VI muscular dystrophies.