Translational program for molecular therapeutics in DMD

DMD 分子治疗转化计划

基本信息

批准号：
7197513
负责人：
HANSELL H STEDMAN
金额：
$ 104.41万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7197513
关键词：
Achievement Address Age Animal Model Applications Grants Blood Vessels Canis familiaris Clinical Clinical Research Clinical Trials Data Derivation procedure Development Disclosure Disease Distal Doctor of Medicine Dose Duchenne muscular dystrophy Dystrophin Engineering Gene Transfer Genetic Hereditary Disease Homologous Gene Human Resources Industry Informed Consent Infusion procedures Injection of therapeutic agent Institutes Investigation Investigational New Drug Application Investments Laboratories Limb structure Measures Methods Modality Molecular Monitoring Clinical Trials Muscle Muscle Fibers Muscular Dystrophies Outcome Parents Participant Pathology Patients Phase Process Proteins Range Reagent Relative (related person)Research Research Design Research Personnel Resources Risk Scientist Series Staging Structure Technology Therapeutic TimeLine Tissues Toxic effect Toxicology Transgenes Treatment Efficacy United States Food and Drug Administration Utrophin abstracting adeno-associated viral vector base design expectation experience infancy man mouse model muscle strength programs scale up spelling technology development transduction efficiency vector

项目摘要

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.

描述（由申请人提供）：Duchenne肌肉营养不良是人中最常见的致命遗传疾病之一。我们对疾病分子基础的理解的进展与分子治疗领域的技术发展平行。术的肌营养不良蛋白，DMD基因产物及其常染色体同源物乌托蛋白的工程版本已被证明可预防DMD小鼠模型中的肌肉变性。 P.I.项目的实验室已经开发了一种高效且安全的模态，用于狗的肢体转移。在非营养不良的狗中进行的研究表明，转导效率接近狗肢中的100％的肌肉纤维，而在AAV背景下使用自转基因的研究则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媒介和血管递送技术的合并能力，以在DMD大型动物模型中实现肌营养不良蛋白缺乏症的广泛遗传互补。我们将采用客观的疗效和毒性测量方法来分析优化的向量在首选输液方法的背景下，从而为临床研究的合理设计提供了信息。拟议的实验计划的中心作用是与Duchenne肌肉营养不良有关的技术发展，期望与更广泛的遗传疾病范围的间接相关性，包括但不限于其他形式的肌肉营养不良。因此，该提案要求在基础科学家，临床科学家，统计学家和合作者之间进行丰富经验，并在基础科学家，临床科学家，统计学家和合作者之间进行合作，重申的过程。解决的问题包括：临床研究的适当起始剂量是什么？相对于退化过程的阶段的治疗窗口是什么？矢量可以安全有效地重新启动吗？扩大规模后，对治疗益处的适当期望是什么？在翻译过程中是否发现了任何不可预见的风险？该提案的结构旨在满足技术开发过程的需求，实验计划围绕实现明确的里程碑的实现为中心，如果适合将调查新药申请提交FDA，则最终达到最终形式。