Translational program for molecular therapeutics in DMD

描述（申请人提供）：杜氏肌营养不良症是人类最常见的致死性遗传疾病之一，我们对该病分子基础的理解随着分子治疗领域技术的发展而不断进步。工程化版本的肌营养不良蛋白，DMD基因产物，及其常染色体同源物肌营养不良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安全的犬肢全基因转移方法。在非营养不良的狗中的研究已经揭示了狗肢体中接近100%的肌纤维的转导效率，而在AAV背景下使用自身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载体和血管递送技术的组合能力，在DMD的大型动物模型中实现抗肌萎缩蛋白缺陷的广泛遗传互补。我们将使用疗效和毒性的客观指标来分析首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。拟议的实验计划的中心重点是与杜氏肌营养不良症相关的技术开发，期望与更广泛的遗传疾病（包括但不限于其他形式的肌营养不良症）间接相关。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行业经验的合作者之间进行合作和交流。讨论的问题包括：临床研究中载体的适当起始剂量是多少？相对于退行性过程的阶段，治疗窗口是什么？带菌者能否安全有效地重新接种？扩大规模后对治疗获益的适当预期是什么？在翻译过程中是否识别出任何不可预见的风险？该提案旨在满足技术开发过程的需求，实验计划以实现明确定义的里程碑为中心，最终在适当时向FDA提交研究性新药申请。

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.