CT GalNAc Transferase Gene Theraphy For DMD

项目2（DMD的CT GalNAc转移酶基因疗法）旨在将有充分证据证明的 原理研究表明，这种转基因可以抑制肌营养不良症， 通过局部血管输送方案，初步研究表明，这种转基因 可以抑制杜氏肌营养不良症（DMD）的mdx模型中的疾病发展， 用于先天性肌营养不良1A（MDC 1A）的dyW模型。这笔赠款将提供原则证明 使用rAAVS（rh.74）-CT GalNAc转移酶局部血管内递送至下肢的数据 通过股动脉灌注肌肉。这种局部血管输送方案将有助于 通过使用最适合于该目的的AAV血清型和使用肌肉特异性启动子来确保 组织特异性表达。目标1将提供mdx小鼠（DMD模型）的原理数据证明， 表明抑制骨骼肌病理和肌肉生理的功能矫正。目的2 将证明拟用于拟定临床试验的局部血管输送方案是安全的， 在非人灵长类动物中有效，并提供有关生物分布、药理学/毒理学和局部分布的必要数据。 转基因表达这一目标还将解决成功的潜在障碍，如免疫反应， 病毒衣壳和转基因以及中和抗体的潜在抑制。这些数据将 提供临床有效性和安全性的主要证据证明，使该疗法达到 IND与FDA的会议，目的是开发一种用于肢体局部血管输送的治疗药物。 目标3涉及这一申请过程的所有方面。

Project 2 (CT GalNAc transferase gene therapy for DMD) seeks to translate well-documented proof of principle studies showing this transgene can inhibit muscular dystrophy to treat skeletal muscles of the lower limb via a localized vascular delivery protocol. Preliminary studies are provided showing that this transgene can inhibit the development of disease both in the mdx model of Duchenne muscular dystrophy (DMD) and for the dyW model of Congenital muscular dystrophy 1A (MDC1 A). This grant will provide proof of principle data using localized intravascular delivery of the rAAVS (rh.74)-CT GalNAc transferase to lower limb muscles through perfusion of the femoral artery. This localized vascular delivery protocol will be facilitated by the use of an AAV serotype best suited for this purpose and use of a muscle-specific promoter to insure tissue-specific expression. Aim 1 will provide proof of principle data in the mdx mouse, a model for DMD, demonstrating inhibition of skeletal muscle pathology and functional correction of muscle physiology. Aim 2 will demonstrate the localized vascular delivery protocol to be used in the proposed clinical trial is safe and effective in the non-human primate, and provide necessary data on biodistribution, pharm/tox, and localized transgene expression. This Aim will also address potential barriers to success, such as immune response to the viral capsid and transgene as well as potential inhibition by neutralizing antibodies. These data will provide the proof of principle evidence of clinical efficacy and safety required to bring this therapy to a pre- IND meeting with the FDA, with the goal of developing a therapeutic for regional vascular delivery in the limb. Aim 3 involves all aspects of this application process.