Toward a mitochondrial therapy of collagen VI muscular dystrophies

Muscular dystrophies are genetic, progressive diseases for which no routine effective therapies are yet 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). Impaired removal of defective mitochondria amplifies the defect and worsens the damage. We have also identified further targets for pharmacological intervention such as excessive oxidative stress and calcium accumulation in the mitochondria of affected muscles; discovered that muscle regeneration and differentiation is impaired; and observed that muscle-derived cells from patients spontaneously attenuate mitochondrial dysfunction during culture. So far 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 will (i) continue testing the efficacy of PTP-active derivatives of CsA that do not cause immunosuppression but are effective in the mouse model and in patients' cells; and (ii) test novel treatments based on the new targets mentioned above, with the goal of defining and validating an effective "combinatorial" therapy of human Collagen VI muscular dystrophies.