Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.
Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases.
Merlini
Luciano
L
Department of Experimental and Diagnostic Medicine, Section of Medical Genetics, University of Ferrara, I-44100 Ferrara, Italy.
Angelin
Alessia
A
Tiepolo
Tania
T
Braghetta
Paola
P
Sabatelli
Patrizia
P
Zamparelli
Alessandra
A
Ferlini
Alessandra
A
Maraldi
Nadir M
NM
Bonaldo
Paolo
P
Bernardi
Paolo
P
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D002648:Child; D024142:Collagen Type VI / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009135:Muscular Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D024142:Collagen Type VI; D016572:Cyclosporine