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: 8032751
• 负责人: Jerry Roy Mendell
• 金额: $ 31.63万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032751
• 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; 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.

项目摘要（请参阅说明）：肌营养不良蛋白特异性T细胞对小鼠和公爵蛋白肌肉肌营养不良症（DMD）的小鼠和狗模型的原始研究的含义已经确定基因替代疗法是一种有希望的治疗策略。试图将从临床前学到的宗旨应用到临床方案中学到的宗旨并不能预测靶向新型表位的肌肉纤维下游肌肉纤维下游下游的肌营养不良蛋白特异性的T细胞。在一种情况下，这些是在恢复纤维上表达的，这一发现与预测这些纤维具有耐受作用的公理相反。另一种治疗范式是庆大霉素诱导的突变抑制，事实证明是令人困惑的，因为肌营养不良蛋白特异性的T细胞是在治疗后血液和肌肉分离出来的。这些观察结果需要进一步研究，以在DMD的基因校正策略中取得成功。在AIM 1中，我们将表征具有良好表征突变的DMD患者的血液和肌肉中肌营养不良蛋白特异性T细胞的特性 确定有多少患者表现出对肌营养不良蛋白的细胞免疫力，并定义了突变性肌营养不良蛋白中的同源自位观型的位置。我们将检查肌营养不良蛋白特异性的CD4+和CD8+ T细胞的效应子fimctions。在AIM 2中，我们将专门研究糖皮质激素在调节T细胞反应中指定的三个月治疗计划中的作用。在这里，我们预计T细胞表型会改变效应子/炎症为调节/抑制器的作用。在AIM 3中，我们将使用AAV.MCK.Micro-Dystrophin进行血管递送临床基因转移研究。我们可以通过将转基因的血管递送到恒河猕猴的特定腿部肌肉来实现高水平的肌肉纤维转导。这为临床功效奠定了基础。该研究的纳入标准包括基于先前经验的当前确定的免疫屏障，并将增加项目1和2中出现的发现。