Toward A Mitochondrial Therapy Of Muscular Dystrophies: From Mouse Model To Clinial Trial
Paolo Bernardi
Biomedical Sciences, University of Padova, Italy
Abstract:
Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM) are muscle diseases due to mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model lacking collagen VI [1] revealed the existence of a Ca2+-mediated dysfunction of mitochondria and the sarcoplasmic reticulum [2]. A key event is inappropriate opening of the mitochondrial permeability transition pore (PTP), an inner membrane high-conductance channel [3]. Consistently, Col6a1-/- mice could be cured with cyclosporin A through inhibition of cyclophilin D, a matrix protein that sensitizes the PTP to opening [3], a remarkable finding that has recently been extended to a severe, UCMD-like disease in zebrafish [4]. Genetic proof of the pathogenic role of the PTP was obtained by crossing Col6a1-/- myopathic mice with Ppif-/- mice (Ppif is the mouse gene encoding for cyclophilin D) [5], as the double null mice displayed a striking recovery from muscle pathology [6]. Studies of myoblasts from UCMD and BM patients demonstrated a latent mitochondrial dysfunction irrespective of the genetic lesion responsible for the lack (or the alteration) of collagen VI [7]. These studies provided the rationale for a pilot trial with cyclosporin (Cs) A in patients affected by UCMD and BM. All patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both these pathological signs were largely normalized after 1 month of CsA administration, which also increased muscle regeneration [8]. These results indicate that mitochondrial dysfunction plays a critical role in human muscle diseases in vivo; and they represent an important proof of principle that hereditary muscle diseases can be cured with proper drugs downstream of the genetic lesion if the pathogenetic mechanisms are understood. Since the mouse model can be cured with a non-immunosuppressive derivative of CsA [9]; and since the PTP is also involved in the pathogenesis of other mouse models of muscular dystrophy [10], these studies may open new perspectives for the therapy of muscular dystrophies and provide a useful example of how translational medicine can rapidly move from animal models to treatment of human diseases.
[5] Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M.A., and Bernardi, P. (2005) J. Biol. Chem. 280, 18558-18561.
[6] Palma, E., Tiepolo, T., Angelin, A., Sabatelli, P., Maraldi, N.M., Basso, E., Forte, M.A., Bernardi, P., and Bonaldo, P. (2009) Hum. Mol. Genet. 18, 2024-2031.
[7] Angelin, A., Tiepolo, T., Sabatelli, P., Grumati, P., Bergamin, N., Golfieri, C., Mattioli, E., Gualandi, F., Ferlini, A., Merlini, L., Maraldi, N.M., Bonaldo, P., and Bernardi, P. (2007) Proc. Natl. Acad. Sci. USA 104, 991-996.
[8] Merlini, L., Angelin, A., Tiepolo, T., Braghetta, P., Sabatelli, P., Zamparelli, A., Ferlini, A., Maraldi, N.M., Bonaldo, P., and Bernardi, P. (2008) Proc. Natl. Acad. Sci. USA 105, 5225-5229.
[9] Tiepolo, T., Angelin, A., Palma, E., Sabatelli, P., Merlini, L., Nicolosi, L., Finetti, F., Braghetta, P., Vuagniaux, G., Dumont, J.M., Baldari, C.T., Bonaldo, P., and Bernardi, P. (2009) Br. J Pharmacol. 157, 1045-1052.
