The Implications of Dystrophin-Specific T cells for DMD gene Correction

肌营养不良蛋白特异性 T 细胞对 DMD 基因校正的意义

• 批准号: 8377171
• 负责人: Jerry Roy Mendell
• 金额: $ 36.7万
• 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/8377171
• 关键词: Address; Blood; Blood Circulation; Blood Vessels; CD8B1 gene; Canis familiaris; Cellular Immunity; Clinical Protocols; Clinical Trials; Disease; Duchenne muscular dystrophy; Dystrophin; Enrollment; Ensure; Epitopes; Exhibits; Fiber; Follow-Up Studies; Frequencies; Gene Expression; Genes; Gentamicins; Glucocorticoids; Goals; Immune; Immune system; Immunity; Induced Mutation; Inflammatory; Instruction; Knowledge; Learning; Leg; Location; Macaca mulatta; Modeling; Mus; Muscle; Muscle Fibers; Muscular Dystrophies; Mutate; Mutation; Pathogenesis; Patients; Phase; Phenotype; Predictive Factor; Property; Proteins; Research; Role; Staging; System; T cell response; T-Lymphocyte; Testing; Transgenes; base; clinical efficacy; effective therapy; experience; follow-up; gene correction; gene replacement; gene replacement therapy; gene therapy; inclusion criteria; micro-dystrophin; miniaturize; novel; pre-clinical; success; transgene expression; treatment program; treatment strategy

PROJECT SUMMARY (See instructions): The Implications of Dystrophin-Speclfic T cells for DMD Gene Correction Proof-of-principle studies in mouse and dog models of Ducheime muscular dystrophy (DMD) have established that gene replacement therapy is a promising treatment strategy. Attempts to apply the tenets learned from pre-clinical to clinical protocols did not predict dystrophin-specific T cells targeting novel epitopes on muscle fibers downstream of the mutation. In one case these were expressed on revertant fibers, a finding contrary to the axiom that forecasts a tolerizing role for these fibers. Another treatment paradigm, gentamicin-induced mutation suppression, proved equally confounding because dystrophin-specific T cells were isolated fi-om the blood and muscle following treatment. These observations require further study to achieve success in gene correction strategies for DMD. In Aim 1 we will characterize the properties of dystrophin-specific T cells in the blood and muscle of DMD patients with well characterized mutations to determine how many patients exhibit cellular immunity to dystrophin and define the location of cognate selfepitopes within the mutated dystrophin protein. We will examine the effector fimctions of CD4+ and CD8+ T cells that are dystrophin specific. In Aim 2 we will look specifically at the role of glucocorticoids in modulating T cell response in a designated three-month treatment program of naive subjects. Here we anticipate a T cell phenotype change fi-om effector/inflammatory to a regulatory/suppressor role. In Aim 3 we will perform a vascular delivery clinical gene transfer study using AAVS.MCK.micro-dystrophin. We can achieve high levels of muscle fiber transduction through vascular delivery of transgene to specific leg muscles in the rhesus macaque. This sets the stage for clinical efficacy. The study inclusion criteria include currently identified immune barriers based on prior experience and will add findings that emerge from Projects 1 and 2.

项目总结（见说明书）：抗肌营养不良蛋白特异性T细胞对DMD基因校正的意义在小鼠和狗的Ducheime肌营养不良（DMD）模型中进行的原理验证研究已经确定基因替代疗法是一种很有前途的治疗策略。将从临床前学到的原则应用于临床方案的尝试并不能预测针对突变下游肌肉纤维上的新表位的抗肌萎缩蛋白特异性T细胞。在一种情况下，这些纤维在反向纤维上表达，这一发现与预测这些纤维的耐受性作用的公理相反。另一种治疗模式，庆大霉素诱导的突变抑制，被证明同样令人困惑，因为治疗后从血液和肌肉中分离出抗营养不良蛋白特异性T细胞。这些观察结果需要进一步研究，以实现DMD基因校正策略的成功。在Aim 1中，我们将描述DMD患者血液和肌肉中肌营养不良蛋白特异性T细胞的特性