COLLAGEN VI MYOPATHIES: FROM MOUSE THERAPY TO HUMAN TRIALS

Muscular dystrophies are genetic, progressive diseases for which no therapy is currently available. We have discovered why muscle fibers degenerate in a mouse model of two human muscular dystrophies caused by abnormalities of Collagen VI (CVI), Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). The absence of CVI has a major impact inside the fiber by triggering a short circuit in the cell's energy generators, the mitochondria. The short circuit is caused by opening of a channel called the "Permeability Transition Pore" (PTP), which can be blocked by the drug cyclosporin A. By treating mice with cyclosporin A we have blocked the short circuit and cured the disease, an important proof of principle that genetic muscular diseases can be cured with drugs. At variance from the mouse model, however, UCMD and BM are genetically and clinically heterogeneous. The key question that we would like to address with our future studies is to what extent the pathogenesis of the human diseases coincides with that caused by lack of CVI in the mouse. In order to answer this question we will carry out a series of studies on biopsies and on cells obtained from UCMD and BM patients. The parallel recruitment, assessment and selection of patients will put us in condition to start a full clinical trial of cyclosporin A in the treatment of human CVI diseases.