Gene delivery of MG53 for muscle membrane repair and functional improvement in a

肌细胞膜完整性缺陷与各种类型的肌营养不良症（MDs）有关。肌营养不良蛋白（dystrophin）基因突变导致Duchenne和Becker肌营养不良症（DMD和BMD），而肌聚糖（SG）基因突变导致肢体带状肌营养不良症（LGMDs）。今天，已经确定了30多种不同的基因导致不同类型的MD，它们都是罕见的（孤儿）疾病。然而，大多数MDs都有类似的肌膜损伤病理后果，如血清创造性激酶（CK）活性升高，肌纤维深度变性，肌肉萎缩和无力。因此，一种旨在修复渗漏细胞膜而不是针对每种特定基因突变的治疗策略应该对许多类型的MD有益。针对肌肉膜修复和重塑的基因治疗显示出希望。长期目标是使用MG53恢复任何营养不良肌肉的肌膜完整性，无论其遗传或获得性起源如何。本研究的直接目标是确定通过AAV8系统基因递送MG53（膜修复机制的重要组成部分）是否可以有效地在体内启动肌膜修复，系统性地挽救骨骼肌功能，并在三角洲肌糖缺失的叙利亚仓鼠模型（一种成熟的肌肉萎缩和充血心力衰竭动物模型）中显著改善整体健康状况。有两个具体目的：1)研究AAV8全身递送后hMG53在to -2仓鼠模型中介导的长期肌膜修复；2)探讨AAV8-hMG53全身给药后to -2仓鼠的组织病理、生理及全身功能改善情况。

Defects in muscle cell membrane integrity have been linked to various types of muscular dystrophies (MDs). Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies (DMD and BMD), while mutations in sarcoglycan (SG) genes because limb girdle muscular dystrophies (LGMDs). Today, more than 30 different genes have been identified to cause different types of MD, and they are all rare (orphan) diseases. However, the majority of MDs share similar pathological consequences from sarcolemma damage, such as elevated serum creative kinase (CK) activity, profound myofiber degeneration, and muscle wasting and weakness. Therefore, a therapeutic strategy that aims at repairing the leaky cell membranes instead of targeting each specific genetic mutation should be beneficial to many types of MD. Gene therapy targeted at muscle membrane repair and remodeling shows promise. The long- term goal is to use MG53 to restore sarcolemma integrity to any dystrophic muscle, irrespective of the hereditary or acquired origin. The immediate goal of this proposal is to determine whether systemic gene delivery of MG53 (an essential component of the membrane repair machinery) by AAV8 can render efficient in vivo initiation of sarcolemma repair, systemic rescue of skeletal muscle function, and substantial improvement of overall health in a delta-sarcoglycan-deficient Syrian hamster model, a well-established muscular dystrophy and congestive heart failure animal model. There are two specific aims: 1) to study long-term muscle membrane repair mediated by hMG53 in the TO-2 hamster model after AAV8 systemic delivery; 2) to investigate the histopathology, physiology, and whole-body functional improvement in TO-2 hamsters after AAV8-hMG53 systemic delivery.