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

MG53 的基因递送用于肌肉膜修复和功能改善

基本信息

批准号：
8058733
负责人：
Bo He
金额：
$ 1.99万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2011-10-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8058733
关键词：
Adhalin Aftercare Alternative Therapies Animal Model Becker Muscular Dystrophy Biochemical Biodistribution Biological Candidate Disease Gene Cell membrane Congestive Heart Failure Creatine Kinase Data Defect Dependovirus Disease Disease model Dystrophin Event Extravasation Gene Delivery Gene Expression Gene Mutation Gene Transfer Genes Goals Hamsters Health Histopathology Human Inherited Injury Investigation Limb-Girdle Muscular Dystrophies Link Longitudinal Studies Mediating Membrane Mesocricetus auratus Modeling Morbidity - disease rate Muscle Muscle Cells Muscle function Muscular Dystrophies Mutation Necrosis Orphan Disease Pathology Pattern Phosphotransferases Physiology Protein Family Proteins Recruitment Activity Reporting Research Sarcoglycans Sarcolemma Serotyping Serum Site Skeletal Muscle System TRIM Motif Testing Therapeutic Therapeutic Effect Toxic effect Treatment Efficacy Vesicle base delta Sarcoglycan dosage extracellular functional improvement gene therapy improved in vivo intraperitoneal intravenous injection method development mortality muscle degeneration non-genetic novel therapeutic intervention overexpression prevent promoter repaired response restoration success therapeutic gene vector wasting

项目摘要

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.

肌细胞膜完整性的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。