CT GalNAc Transferase Gene Theraphy For DMD

CT GalNAc 转移酶基因治疗 DMD

• 批准号: 7328073
• 负责人: PAUL Taylor MARTIN
• 金额: $ 31.7万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328073
• 关键词: Address; Age; Animal Model; Animals; Anterior; Antigens; Biodistribution; Blood Circulation; Blood Vessels; CD8B1 gene; Capsid; Carbohydrates; Catheterization; Catheters; Cell Membrane Permeability; Cells; Child; Clinical; Clinical Trials; Coupled; Data; Dependovirus; Development; Disease; Disease Progression; Dose; Duchenne muscular dystrophy; Dyes; Dystrophin; Enzymes; Evans blue stain; Gastrocnemius Muscle; Gene Delivery; Gene Transduction Agent; Gene Transfer; Generations; Genes; Goals; Golgi Apparatus; Grant; Hereditary Disease; Human; Immune response; Immunity; Immunosuppression; Immunosuppressive Agents; Infection; Injury; Intramuscular Injections; Investigational Drugs; Investigational New Drug Application; Laminin; Limb structure; Localized; Longevity; Lower Extremity; Macaca mulatta; Measures; Mediating; Membrane; Methods; Modeling; Monkeys; Mus; Muscle; Muscle Development; Muscle function; Muscular Dystrophies; Myocardium; Outcome; Outcome Measure; Pathology; Patients; Perfusion; Phase; Phase I Clinical Trials; Physiological; Physiology; Polypeptide N-acetylgalactosaminyltransferase; Preparation; Process; Protein Overexpression; Proteins; Protocols documentation; Purpose; Research Institute; Resistance; Route; Safety; Serotyping; Simulate; Skeletal Muscle; Skeletal system; Synapses; System; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Tissues; Toxicology; Transferase Gene; Transgenes; Translating; Treatment Protocols; United States Food and Drug Administration; Viral; Virus; Week; boys; clinical efficacy; cohort; congenital muscular dystrophy; cytotoxic; design; dosage; femoral artery; functional improvement; gene therapy; glycosyltransferase; immunogenicity; improved; mdx mouse; mouse model; neutralizing antibody; nonhuman primate; postsynaptic; prevent; promoter; research study; response; success; transgene expression; uptake; vector

Project 2 (CT GalNAc transferase gene therapy for DMD) seeks to translate well-documented proof of principle studies showing this transgene can inhibit muscular dystrophy to treat skeletal muscles of the lower limb via a localized vascular delivery protocol. Preliminary studies are provided showing that this transgene can inhibit the development of disease both in the mdx model of Duchenne muscular dystrophy (DMD) and for the dyW model of Congenital muscular dystrophy 1A (MDC1 A). This grant will provide proof of principle data using localized intravascular delivery of the rAAVS (rh.74)-CT GalNAc transferase to lower limb muscles through perfusion of the femoral artery. This localized vascular delivery protocol will be facilitated by the use of an AAV serotype best suited for this purpose and use of a muscle-specific promoter to insure tissue-specific expression. Aim 1 will provide proof of principle data in the mdx mouse, a model for DMD, demonstrating inhibition of skeletal muscle pathology and functional correction of muscle physiology. Aim 2 will demonstrate the localized vascular delivery protocol to be used in the proposed clinical trial is safe and effective in the non-human primate, and provide necessary data on biodistribution, pharm/tox, and localized transgene expression. This Aim will also address potential barriers to success, such as immune response to the viral capsid and transgene as well as potential inhibition by neutralizing antibodies. These data will provide the proof of principle evidence of clinical efficacy and safety required to bring this therapy to a pre- IND meeting with the FDA, with the goal of developing a therapeutic for regional vascular delivery in the limb. Aim 3 involves all aspects of this application process.

项目2(DMD的CT GalNAc转移酶基因治疗)试图将记录良好的证据转化为 原理研究表明，该转基因可以抑制肌营养不良症治疗低位骨骼肌 通过局部血管输送方案进行肢体移植。初步研究表明，这种转基因 能抑制Duchenne肌营养不良症(DMD)的MDX模型和 用于先天性肌营养不良症1A(MDC1A)的DyW模型。这笔赠款将提供原则性证明。 局部血管内注射rAAVS(Rh.74)-CT GalNAc转移酶到下肢的数据 肌肉通过股动脉的灌流。这种局部的血管输送方案将被促进 通过使用最适合于此目的的AAV血清型和使用肌肉特异性启动子来确保 组织特异性表达。AIM 1将提供MDX小鼠的原理数据证据，DMD的模型， 表现出对骨骼肌病理的抑制和肌肉生理的功能矫正。目标2 将证明在拟议的临床试验中使用的局部血管给药方案是安全的和 对非人类灵长类动物有效，并提供必要的生物分布、毒物/毒物和本地化数据 转基因表达。这一目标还将解决成功的潜在障碍，如免疫反应 病毒衣壳和转基因以及中和抗体的潜在抑制。这些数据将 提供将该疗法推向临床前所需的临床有效性和安全性的原则证据证据 IND与FDA的会议，目标是开发一种治疗肢体局部血管输送的药物。 AIM 3涉及申请过程的方方面面。