Dystrophin Restoration

肌营养不良蛋白恢复

• 批准号: 7691708
• 负责人: Jerry Roy Mendell
• 金额: $ 34.19万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7691708
• 关键词: Accounting; Address; Advisory Committees; Animals; B-Lymphocytes; Biodistribution; Blood Circulation; Blood Vessels; CD8B1 gene; Capsid; Catheters; Cells; Clinical; Clinical Data; Clinical Protocols; Clinical Trials; Complex; Consent Forms; Cytotoxic T-Lymphocytes; Data; Disease; Distal; Dose; Drug usage; Duchenne muscular dystrophy; Dyes; Dystrophin; Ensure; Environment; Evans blue stain; Exhibits; Face; Factor IX; Fluorescence; Gene Delivery; Gene Expression; Gene Transfer; Generations; Genes; Goals; Hand; Head; Histocompatibility Antigens Class I; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunosuppression; Intramuscular; Intramuscular Injections; Investigational Drugs; Investigational New Drug Application; Iron binding capacity measurement; Literature; Macaca mulatta; Marketing; Mediating; Membrane; Modeling; Monkeys; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Mycophenolate Mofetil/Tacrolimus; Organ Transplantation; Outcome; Outcome Measure; Patients; Pediatric Hospitals; Perfusion; Personal Satisfaction; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Physiological; Polypeptide N-acetylgalactosaminyltransferase; Population; Positioning Attribute; Prednisone; Preparation; Primates; Probability; Property; Proteins; Protocols documentation; Purine Antagonist; Recombinant DNA; Recovery of Function; Replacement Therapy; Research Ethics Committees; Research Personnel; Route; Safety; Serotyping; Simulate; Staging; Surface; System; T-Cell Activation; T-Lymphocyte; Tacrolimus; Target Populations; Testing; Therapeutic immunosuppression; Time; Toxicology; Transgenes; Treatment Protocols; United States Food and Drug Administration; Upper arm; Viral; Virus; Week; Work; base; boys; cellular transduction; cohort; design; femoral artery; gene delivery system; gene replacement; gene therapy; gene therapy clinical trial; immunogenicity; improved; inhibitor/antagonist; man; manufacturing process; mdx mouse; micro-dystrophin; mini-dystrophin; mycophenolate mofetil; neutralizing antibody; nonhuman primate; patient safety; pre-clinical; promoter; radiologist; response; restoration; success; time interval; uptake; vector

Currently, proof-of-principle studies have established that gene replacement therapy represents a promising means of treatment for Duchenne muscular dystrophy (DMD). We have moved forward in a clinical phase I safety gene therapy trial for this disease by intramuscular delivery of an rAAV mini-dystrophin gene. It is acknowledged throughout the field that vascular delivery, reaching many muscle groups, is our best hope for improving patient function. In preliminary discussions with the FDA in preparation for this U54, we were encouraged to move forward with gene delivery through the circulation, being mindful of potential safety concerns. Our current project takes these considerations into account. We have found in preliminary studies that rAAVS can deliver micro-dystrophin efficiently to muscle in the mdx mouse. Further, we have data that predicts that this AAV serotype can cross species lines with delivery of a transgene to a large animal species. This sets the stage for our current proposal, integrating safety and efficacy concerns of vascular delivery. Our plan to bring this to IND and a phase I safety trial for vascular delivery is as follows: The first goal for this project (AIM1) is to establish that the micro-dystrophin transgene that we designed (based on the best information from the literature) can functionally improve dystrophic muscle. For our current IND we used an isolated muscle in the mdx mouse to prove functional efficacy and we will follow this example in this proposal. For our second goal (AIM 2) we will deliver the rAAVS.micro-dystrophin to the rhesus macaque. There have been many issues raised regarding the immunogenicity of both AAV and the cargo it carries. The rhesus macaque permits us to address all of these issues in an environment that closely simulates a clinical trial. Two concerns are at hand, safe passage of virus to achieve transduction and safety to the patient avoiding undesirable spread of virus. Thus, we will deliver our viral construct through a balloon catheter placed in the femoral artery. We will also test appropriateness of immunosuppression regimens for gene delivery using some monkeys with pre-existing immunity to AAV and others naTve to the virus. In the final AIM 3, we will do the toxicology/biodistribution studies in accordance with our discussions with FDA. The information derived from this project will permit us to submit an IND for a phase I safety trial in DMD boys.

目前，原则研究证明，基因替代疗法代表了一种有希望的 Duchenne肌营养不良症（DMD）的治疗方法。我们已经在临床第一阶段前进 通过肌内递送RAAV迷你肺炎蛋白基因的安全基因治疗试验。这是 在整个领域都承认，到达许多肌肉群的血管分娩是我们对 改善患者功能。在与FDA的初步讨论中为此U54做准备，我们是 鼓励通过流通进行基因递送，注意潜在的安全 关注。我们当前的项目考虑了这些注意事项。我们在初步中发现 RAAV可以在MDX小鼠的肌肉中有效地输送微肺炎的研究。此外，我们还有 预测该AAV血清型可以与将转基因传递到大的数据的数据 动物物种。这为我们当前的建议奠定了基础，整合了安全性和效力问题 血管递送。我们将其引入IND的计划以及对血管交付的I期安全试验如下： 该项目的第一个目标（AIM1）是确定我们设计的微型链霉素转基因 （根据文献的最佳信息）可以在功能上改善营养不良的肌肉。为我们 电流IND我们在MDX小鼠中使用孤立的肌肉来证明功能疗效，我们将遵循这一点 该提议中的示例。对于我们的第二个目标（目标2），我们将把raavs.micro-dystrophin交付给 恒河猕猴。关于AAV和AAV的免疫原性提出了许多问题 它载有货物。恒河猴允许我们在一个环境中解决所有这些问题 密切模拟临床试验。目前有两个问题，安全地通过病毒来实现转导 和对患者的安全性，避免了病毒的不良传播。因此，我们将提供病毒式结构 通过放置在股动脉中的气球导管。我们还将测试适当性 使用一些对AAV免疫的猴子进行基因递送的免疫抑制方案，并 其他人则是病毒。在最终目标3中，我们将根据一项毒理学/生物分布研究 在我们与FDA的讨论中。从该项目中得出的信息将使我们能够提交IND DMD男孩的第一阶段安全试验。