A Naturally Occurring Human Minidysferlin Protein Repairs Sarcolemmal Lesions in a Mouse Model of Dysferlinopathy

作者：Krahn Martin; Wein Nicolas; Bartoli Marc; Lostal William; Courrier Sebastien; Bourg Alibert Nathalie; Nguyen Karine; Vial Christophe; Streichenberger Nathalie; Labelle Veronique; DePetris Danielle; Pecheux Christophe; Leturcq France; Cau Pierre; Richard Isabelle; Levy Nicolas^*

来源：Science Translational Medicine, 2010, 2(50): 50ra69.

DOI：10.1126/scitranslmed.3000951

Dysferlinopathies are autosomal recessive, progressive muscle dystrophies caused by mutations in DYSF, leading to a loss or a severe reduction of dysferlin, a key protein in sarcolemmal repair. Currently, no etiological treatment is available for patients affected with dysferlinopathy. As for other muscular dystrophies, gene therapy approaches based on recombinant adeno-associated virus (rAAV) vectors are promising options. However, because dysferlin messenger RNA is far above the natural packaging size of rAAV, full-length dysferlin gene transfer would be problematic. In a patient presenting with a late-onset moderate dysferlinopathy, we identified a large homozygous deletion, leading to the production of a natural "minidysferlin" protein. Using rAAV-mediated gene transfer into muscle, we demonstrated targeting of the minidysferlin to the muscle membrane and efficient repair of sarcolemmal lesions in a mouse model of dysferlinopathy. Thus, as previously demonstrated in the case of dystrophin, a deletion mutant of the dysferlin gene is also functional, suggesting that dysferlin's structure is modular. This minidysferlin protein could be used as part of a therapeutic strategy for patients affected with dysferlinopathies.

• 出版日期2010-9-22