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

描述（由申请人提供）：肌细胞膜完整性缺陷与各种类型的肌营养不良症（MD）有关。肌营养不良蛋白基因的突变导致杜氏和贝克肌营养不良症（DMD和BMD），而肌聚糖（SG）基因的突变导致肢带型肌营养不良症（LGMD）。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（孤儿）疾病。然而，大多数MD共享来自肌膜损伤的类似病理学后果，例如血清创造性激酶（CK）活性升高、严重肌纤维变性以及肌肉萎缩和虚弱。因此，旨在修复渗漏的细胞膜而不是针对每个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MG 53来恢复任何营养不良肌肉的肌膜完整性，而不管遗传或获得性起源。该提议的直接目标是确定通过AAV 8的MG 53（膜修复机制的必要组分）的系统性基因递送是否可以在δ-肌聚糖缺陷的叙利亚仓鼠模型（一种完善的肌营养不良和充血性心力衰竭动物模型）中有效地在体内引发肌膜修复、骨骼肌功能的系统性拯救和整体健康的实质性改善。有两个具体目标：1）在T0 -2仓鼠模型中研究在AAV 8全身递送后由hMG 53介导的长期肌膜修复; 2）研究在AAV 8-hMG 53全身递送后T0 -2仓鼠中的组织病理学、生理学和全身功能改善。 公共卫生相关性：该提案的新奇来自于独特的治疗概念，即通过过表达hMG 53来恢复肌膜完整性，而不是靶向导致不同类型肌营养不良症的每个基因突变，从而预防肌营养不良症的表现。MG 53介导的肌膜修复和重塑可能在临床上成为任何肌肉膜渗漏或破坏的替代疗法，包括任何类型的肌营养不良症和其他非遗传性疾病或损伤。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The novelty of this proposal comes from the unique therapeutic concept of preventing the manifestation of muscular dystrophy by overexpressing hMG53 to restore muscle membrane integrity instead of targeting each genetic mutation responsible for causing the different types of muscular dystrophy. MG53-mediated muscle membrane repair and remodeling could clinically become an alternative therapy for any membrane leakage or disruption of muscle, including any type of muscular dystrophy and other non-genetic diseases or injuries.