Translational program for molecular therapeutics in DMD

描述（由申请人提供）：杜氏肌营养不良症是人类最常见的致命遗传性疾病之一。我们对疾病分子基础的理解的进步与分子治疗领域的技术发展是同步的。工程版本的肌营养不良蛋白，DMD基因产物，和它的常染色体同系物肌营养蛋白已被证明可以防止DMD小鼠模型中的肌肉变性。P.I.项目的实验室已经开发出一种高效和安全的方式，用于狗的全肢体基因转移。对非营养不良犬的研究表明，犬肢肌纤维的转导效率接近100%，而在AAV背景下使用自我转基因的研究提供了长期稳定性的证据。为了解决翻译过程中的一系列关键步骤，我们将利用AAV载体和血管传递技术的联合力量，在大型DMD动物模型中实现肌营养不良蛋白缺乏的广泛遗传互补。我们将使用疗效和毒性的客观测量来分析优选输注方法背景下的优化载体，从而为临床研究的合理设计提供信息。拟议实验计划的中心主旨是与杜氏肌营养不良相关的技术开发，期望与更广泛的遗传疾病间接相关，包括但不限于其他形式的肌营养不良。因此，该提案要求在基础科学家、临床科学家、统计学家和具有丰富工业经验的合作者之间进行合作、反复的思想和试剂交流过程。涉及的问题包括：临床调查的适当媒介起始剂量是多少？与退行性过程的阶段相关的治疗窗口是什么？能否安全有效地重新接种病媒？在扩大规模后，对治疗收益的适当期望是什么？在翻译过程中是否发现了任何不可预见的风险？该提案的结构是为了满足技术开发过程的需要，实验计划以实现明确的里程碑为中心，如果适当的话，在向FDA提交研究性新药申请时达到高潮。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy is one of the most common lethal genetic diseases in man. Progress in our understanding of the molecular basis of the disease has been paralleled by technological developments in the field of molecular therapy. Engineered versions of dystrophin, the DMD gene product, and its autosomal homologue utrophin have been shown to protect against muscle degeneration in mouse models for DMD. The laboratory of the project P.I. has developed a highly efficient and safe modality for limb-wide gene transfer in the dog. Studies in non-dystrophic dogs have revealed a transduction efficiency approaching 100% of the muscle fibers in the dog limb, while studies using self-transgenes in the context of AAV provide evidence of long-term stability. To address a series of critical steps in the translational process, we will harness the combined power of AAV vector and vascular delivery technology to achieve widespread genetic complementation of dystrophin deficiency in a large animal model for DMD. We will use objective measures of efficacy and toxicity to analyze an optimized vector in the context of a preferred infusion approach, thereby informing the rational design of clinical studies. The central thrust of the proposed experimental plan is technology development relevant to Duchenne muscular dystrophy, with the expectation of indirect relevance for a wider range of genetic disorders, including but not limited to other forms of muscular dystrophy. As such the proposal mandates a cooperative, reiterative process with exchange of ideas and reagents between basic scientists, clinical scientists, statisticians, and collaborators with extensive experience in industry. Questions addressed include: What is the appropriate starting dose of vector for clinical investigation? What is the therapeutic window relative to the stage of the degenerative process? Can the vector be safely and effectively readministered? What are appropriate expectations for therapeutic benefit following scale-up? Are any unforeseen risks are identified during the translational process? The proposal is structured to meet the needs of the technology development process, and the experimental plan is centered around the achievement of well-defined milestones, culminating if appropriate in the submission of an investigational new drug application to the FDA.