Myostatin Inhibition in DMD Dogs by Gene Transfer

描述（由申请人提供）： 在过去的十年中，肌肉生长抑制素，肌肉生长的负调节剂，已成为一个新的治疗目标，许多肌肉退行性疾病，包括杜兴肌营养不良症（DMD）。肌生长抑制素的抑制促进肌肉生长，因此提供了一种间接的方式来补偿肌肉萎缩症（MD）中的肌肉变性，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、递送抑制性蛋白/抗体或AAV基因载体，肌生长抑制素抑制已显示出显著的功效。然而，肌生长抑制素抑制的治疗潜力和安全性尚未在大型动物MD模型，如DMD金毛猎犬肌营养不良症（GRMD）犬中进行评估。我们假设，通过AAV载体基因递送犬肌生长抑制素前肽（肌生长抑制素的天然和特异性抑制剂）将增强GRMD犬的肌肉生长并减少萎缩，改善营养不良性病理并改善肌肉功能。在与DMD犬科动物模型中心的密切合作中，我们建议使用GRMD模型来研究两个具体目标：1）检查后肢区域基因递送后的基因表达和治疗效果; 2）评估全身基因递送后全身基因表达，肌肉生长和全身功能改善。该项目的成功将验证肌生长抑制素前肽在大型动物DMD模型中的作用，并为肌生长抑制素抑制剂基因治疗的临床应用提供技术支持。 公共卫生相关性： 该建议试图通过在大型动物模型中阻断肌肉生长抑制剂（称为肌生长抑制素）来验证杜氏肌营养不良症的治疗策略。它的成功将为肌营养不良症的未来临床应用提供一种使能技术。

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.