Myostatin Inhibition in DMD Dogs by Gene Transfer

描述(由申请人提供)： 在过去的十年里，肌肉生长的负调控因子myostatin已经成为包括Duchene肌营养不良(DMD)在内的许多肌肉退行性疾病的新的治疗靶点。抑制Myostatin促进肌肉生长，因此提供了一种间接补偿肌营养不良症(MD)肌肉退化的方法，而不直接解决特定的遗传缺陷。在许多小鼠MD模型中，通过转基因技术、抑制蛋白/抗体或AAV基因载体的传递，肌肉生长抑素的抑制已经显示出实质性的效果。然而，肌肉抑制素的治疗潜力和安全性尚未在大型动物MD模型中进行评估，如DMD金毛猎犬肌营养不良症(GRMD)。我们推测，通过AAV载体携带犬肌肉生长抑制素前体肽(一种肌肉生长抑制素的天然和特异性抑制物)，可以促进GRMD犬的肌肉生长，减少萎缩，改善营养不良的病理改变，改善肌肉功能。与北卡罗来纳大学教堂山分校的DMD犬模型中心密切合作，我们建议使用GRMD模型来研究两个具体目标：1)检测后肢局部基因输送后的基因表达和治疗效果；2)评估全身基因输送后全身基因表达、肌肉生长和全身功能改善。该项目的成功将在大型动物DMD模型中验证Myostatin前肽，并为Myostatin抑制剂基因治疗未来的临床应用提供一项使能技术。 公共卫生相关性： 这项建议试图通过在大型动物模型中阻断一种名为肌肉生长抑制素的肌肉生长抑制物来验证杜氏肌营养不良症的治疗策略。它的成功将为肌肉营养不良症的未来临床应用提供一项使能技术。

DESCRIPTION (provided by applicant): Over the past decade, myostatin, a negative regulator of muscle growth, has emerged as a novel therapeutic target for a number of muscle degenerative diseases including Duchene muscular dystrophy (DMD). Inhibition of myostatin promotes muscle growth, and therefore offers an indirect way of compensating muscle degeneration in muscular dystrophies (MD) without directly addressing the specific genetic defects. In a number of mouse MD models, myostatin inhibition has demonstrated substantial efficacies by transgenic technology, delivery of inhibitory proteins/antibodies or AAV gene vectors. However, the therapeutic potential and safety of myostatin inhibition has not been evaluated in large animal MD models, such as the DMD golden retriever muscular dystrophy (GRMD) dogs. We hypothesize that gene delivery of a canine myostatin propeptide, a natural and specific inhibitor of myostatin, by AAV vectors would enhance muscle growth and reduce atrophy, ameliorate dystrophic pathologies and improve muscle functions in the GRMD dogs. In close collaboration with the DMD Canine Model Center at UNC Chapel Hill, we propose to use the GRMD model to study two specific aims: 1) to examine gene expression and therapeutic effects after regional gene delivery in the hindlimbs; 2) to evaluate body-wide gene expression, muscle growth and wholebody functional improvement after systemic gene delivery. The success of this project will validate myostatin propeptide in the large animal DMD model and provide an enabling technology for myostatin inhibitor gene therapy for future clinical applications. PUBLIC HEALTH RELEVANCE: This proposal attempts to validate a therapeutic strategy for Duchenne muscular dystrophy by blocking a muscle growth inhibitor, termed myostatin, in a large animal model. Its success will provide an enabling technology for future clinical applications in muscular dystrophies.