Models Core

模型核心(核心C)将为项目1和2提供四个基本的支持要素。 Models Core将负责培育和维护MDX小鼠，以进行两项实验 项目1和2：Duchenne肌营养不良症的MDX小鼠模型是验证基因的关键 此U54申请中所建议的治疗效果。第二，机型核心将提供所有 Mdx小鼠基因功能的生理学评估。它们包括要约人和怪人 指长伸肌的收缩测量。众所周知，这些措施是 在FDA认可的DMD动物模型中受损，因此将为每个 该项目展示了一种具有生理意义的改善肌肉功能的临床措施。 这种验证对于证明有效性至关重要。第三，核心将负责住房和 在两个项目中描述的实验中照顾恒河猴。非人灵长类动物 对于评估较大动物物种的免疫学、分布和疗效是必不可少的，以供审查 食品和药物管理局。第四，核心将在两个MDX中执行和优化区域血管递送方案 小鼠和恒河猴通过rAAVS介导的人微肌营养不良蛋白和CT GAINAc转移酶的表达 通过股动脉将基因输送到下肢肌肉。这其中涉及的技能 传递系统最好通过重复执行来获得。在核心中提供此技术是 对实现两个项目的一致性至关重要，对转基因的一致分布至关重要 在目标肌肉(腓肠肌)内。

The Models Core (Core C) will provide four essential support elements for Projects 1 and 2. First, the Models Core will be responsible for breeding and maintaining mdx mice for experiments described in both projects 1 and 2. The mdx mouse model for Duchenne muscular dystrophy is essential for verifying gene therapeutic efficacy as proposed in this U54 application. Second, the Models Core will provide all physiological assessments of gene function in the mdx mouse. These consist offeree and eccentric contraction measurements of the extensor digitorum longus muscle. These measures are known to be impaired in this FDA accepted animal model for DMD, and thus will provide important criteria for each Project to demonstrate a physiologically significant clinical measure of improvement in muscle function. Such validation is critical for demonstrating efficacy. Third, the core will be responsible for the housing and care of rhesus macaque monkeys for experiments described in both projects. Non-human primate animals are essential to evaluate the immunology, distribution, and efficacy in a larger animal species for review by the FDA. Fourth, the Core will perform and optimize regional vascular delivery protocols, in both the mdx mouse and rhesus macaque, to deliver human micro-dystrophin and CT GAINAc transferase via rAAVSmediated gene delivery to the muscles of the lower limb via the femoral artery. The skills involved in this delivery system are best acquired by repeated performance. Providing this technique in the Core is essential to achieve uniformity for both projects, and is essential for consistent distribution of transgenes within the targeted muscle (gastrocnemius).