Myostatin Inhibition in DMD Dogs by Gene Transfer

通过基因转移抑制 DMD 犬的肌肉生长抑制素

基本信息

批准号：
8504900
负责人：
Xiao Xiao
金额：
$ 30.07万
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：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8504900
关键词：
Address Animal Model Animal Muscular Dystrophy Animals Antibodies Atrophic Attention Autopsy Biopsy Body Size Body Weight Canis familiaris Clinical Clinical Research Collaborations Contracture Contralateral Data Degenerative Disorder Development Disease Progression Duchenne muscular dystrophy Enrollment Evaluation Future Gene Delivery Gene Expression Gene Transfer Genes Genetic Growth Growth Inhibitors Half-Life Health Hindlimb Histopathology Imaging technology Immunoglobulin G In Situ Incidence Individual Infiltration Intravenous Leg Limb structure Longevity Longitudinal Studies Magnetic Resonance Imaging Mediating Methods Modeling Monitor Morbidity - disease rate Mus Muscle Muscle function Muscular Atrophy Muscular Dystrophies Mutation Myopathy Pathology Patients Phase Physical activity Point Mutation Proteins Resistance Safety Technology Testing Therapeutic Therapeutic Effect Transducers Transgenes Transgenic Organisms Treatment Efficacy Variant Veins Wasting Syndrome Work adeno-associated viral vector boys clinical application design effective therapy functional improvement gene replacement gene replacement therapy gene therapy improved inhibitor/antagonist mdx mouse mini-dystrophin muscle degeneration muscular dystrophy mouse model myostatin new therapeutic target novel therapeutics pressure public health relevance success therapeutic development tool transgene expression vector vector biodistribution

项目摘要

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.

描述（由申请人提供）：在过去的十年中，Myostatin是肌肉生长的阴性调节剂，已成为许多肌肉退行性疾病，包括杜尚·肌肉营养不良（DMD）的新型治疗靶标。抑制肌抑制蛋白会促进肌肉生长，因此提供了一种补偿肌肉营养不良（MD）肌肉变性的间接方法，而无需直接解决特定的遗传缺陷。在许多小鼠MD模型中，肌生抑制素抑制作用通过转基因技术，抑制性蛋白/抗体或AAV基因载体的递送表现出很大的效力。但是，在大型动物MD模型中尚未评估肌生抑制蛋白抑制的治疗潜力和安全性，例如DMD金毛寻回犬肌肉营养不良症（GRMD）狗。我们假设通过AAV载体的天然和特异性抑制剂的犬肌抑制剂的基因递送将增强肌肉生长并减少萎缩，改善营养不良的疾病并改善GRMD犬中的肌肉功能。在与UNC Chapel Hill的DMD犬模型中心密切合作，我们建议使用GRMD模型研究两个具体目的：1）检查后肢区域基因递送后基因表达和治疗作用； 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。该项目的成功将在大型动物DMD模型中验证肌生抑制素的丙肽，并为肌生抑制蛋白抑制剂基因疗法提供有利的技术，以实现未来的临床应用。