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命性遗传病之一。随着分子治疗领域的技术发展，我们对这种疾病的分子基础的理解也取得了进展。DMD基因产物Dystrophin的工程化版本及其常染色体同系物utroin已被证明可以保护DMD小鼠模型的肌肉退化。P.I.项目的实验室已经开发出一种高效、安全的狗四肢基因转移方法。对非营养不良狗的研究表明，转导效率接近狗肢体肌肉纤维的100%，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力量，在DMD的大型动物模型中实现Dstrophin缺乏症的广泛遗传互补。我们将使用疗效和毒性的客观测量方法，在首选输液方法的背景下分析优化的载体，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是与Duchenne肌营养不良症相关的技术开发，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症。因此，该提案要求基础科学家、临床科学家、统计学家和具有广泛工业经验的合作者之间进行合作、反复的过程，交流想法和试剂。提出的问题包括：临床研究中合适的载体起始剂量是多少？相对于退变过程的阶段，治疗窗口是什么？能安全有效地重新管理病媒吗？在扩大规模后，对治疗效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求，实验计划的中心是实现明确定义的里程碑，如果合适的话，最终将向FDA提交试验性新药申请。

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.