Barthélémy Florian, Blouin Cédric, Wein Nicolas, Mouly Vincent, Courrier Sébastien, Dionnet Eugénie, Kergourlay Virginie, Mathieu Yves, Garcia Luis, Butler-Browne Gillian, Lamaze Christophe, Lévy Nicolas, Krahn Martin, Bartoli Marc
Aix Marseille Universit é, UMR S 910, Facult é de Médecine de la Timone, Marseille, France.
GMGF, INSERM UMR_ S 910, Marseille, France.
J Neuromuscul Dis. 2015 Sep 2;2(3):281-290. doi: 10.3233/JND-150109.
Dysferlinopathies are a family of disabling muscular dystrophies with LGMD2B and Miyoshi myopathy as the main phenotypes. They are associated with molecular defects in DYSF, which encodes dysferlin, a key player in sarcolemmal homeostasis. Previous investigations have suggested that exon skipping may be a promising therapy for a subset of patients with dysferlinopathies. Such an approach aims to rescue functional proteins when targeting modular proteins and specific tissues.We sought to evaluate the dysferlin functional recovery following exon 32 skipping in the cells of affected patients. Exon skipping efficacy was characterized at several levels by use of in vitro myotube formation assays and quantitative membrane repair and recovery tests. Data obtained from these assessments confirmed that dysferlin function is rescued by quasi-dysferlin expression in treated patient cells, supporting the case for a therapeutic antisense-based trial in a subset of dysferlin-deficient patients.
肌膜蛋白病是一类使人衰弱的肌营养不良症，主要表型为肢带型肌营养不良2B型（LGMD2B）和宫下肌病。它们与DYSF的分子缺陷有关，DYSF编码肌膜蛋白，这是肌膜稳态的关键参与者。先前的研究表明，外显子跳跃可能是治疗一部分肌膜蛋白病患者的一种有前景的疗法。这种方法旨在针对模块化蛋白和特定组织时拯救功能性蛋白。我们试图评估受影响患者细胞中外显子32跳跃后肌膜蛋白功能的恢复情况。通过使用体外肌管形成试验以及定量膜修复和恢复测试，在多个水平上对外显子跳跃效果进行了表征。从这些评估中获得的数据证实，在经治疗的患者细胞中，准肌膜蛋白表达可拯救肌膜蛋白功能，这为在一部分肌膜蛋白缺陷患者中进行基于反义疗法的试验提供了支持。
