MITOCHONDRIAL THERAPY WITH CYCLOSPORINE A IN PATIENTS WITH ULLRICH CONGENITAL MUSCULAR DYSTROPHY

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 one-month pilot trial with CsA in five patients affected by UCMD and BM has proved in vivo the pathogenetic mechanism and its correction. In addition in the muscle biopsy taken after treatment the number of apoptotic cell was decreased while an increased number of regenerating myofibers were detected. Three of these patients have subsequently taken CsA for one more year showing a mild but statistically significant increase in muscle strength. These encouraging results confirm that the primary endpoint (impact of treatment on muscle strength) is a feasible measurement to be made, and indicate that our proposal to continue the trial for one more year is needed to better exploit the therapeutic potential of this pharmacologic approach for the patients with UCMD.