Overcoming Immune Barriers to Gene Correction for Duchenne Muscular Dystrophy

克服杜氏肌营养不良症基因校正的免疫障碍

• 批准号: 8473891
• 负责人: Jerry Roy Mendell
• 金额: $ 126.3万
• 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/8473891
• 关键词: Affect; Aftercare; Biological Assay; Blood Vessels; CD8B1 gene; Cell physiology; Clinical Treatment; Clinical Trials; Duchenne muscular dystrophy; Dystrophin; Education; Environment; Epitopes; Failure; Gene Delivery; Gene Transfer; Glucocorticoids; Goals; Health; Histopathology; Human; Immune; Immune response; Immunity; Immunology; Individual; Length; Mediating; Molecular; Monitor; Muscle; Muscle Cells; Muscular Dystrophies; Nonsense Mutation; Patients; Play; Population; Prevalence; Property; Recombinants; Research; Resources; Role; Safety; Serum; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Transgenes; Vaccines; Walkers; collaborative trial; combat; experience; gene correction; gene therapy; man; micro-dystrophin; neutralizing antibody; pilot trial; programs; response; success; therapeutic target; therapy design

DESCRIPTION (provided by applicant): Potential therapies now entering clinical trials for treatment of Duchenne Muscular Dystrophy include microdystrophin gene transfer (resulting in an internally truncated dystrophin) and suppression of nonsense mutations (resulting in a full-length dystrophin). In recently completed human trials of each, we have identified significant T-cell immune responses directed at dystrophin epitopes in both treated and untreated patients. It is the overall goal of our Wellstone Muscular Dystrophy Cooperative Research Center to identify the prevalence and molecular determinants of this immunity, and to determine what role immune responses to both dystrophin and recombinant AAV may play in the success or failure of gene correction therapies. In pursuit of this goal, we propose a plan that makes use of the extensive expertise and resources of the Centers for Gene Therapy and for Vaccines and Immunity at NCH. In Project 1 (J. R.Mendell, PI), we will characterize the properties and prevalence of dystrophin-specific T-cells in DMD subjects; determine the effect of initiation of glucocorticoid therapy on modulating this response; and assess these responses in a pilot trial of vascular delivery of an AAV8.MCK.micro-dystrophin. In Project 2 (C. Walker, PI), we will assess enhancement of transgene delivery in AAV-immune individuals via transient depletion of serum neutralizing antibodies; define the role the role of CD4-I- and/or CD8+ T cells against a foreign transgene product in clearance of rAAV-transduced myocytes; and determine if transient blockade of T cell activation and expansion facilitates persistent expression of a non-self transgene. The Administrative Core (Core A; J. Mendell, PI) makes use of a cadre of staff with experience in managing collaborative trials and projects in DMD, including first-in-man trials of gene therapy. The Histopathology Core (Core C; Z. Sahenk, PI) will utilize expert staff to provide resources for the analysis of tissue from projects within this and other Weilstone Centers. The Immunology Scientific Core (Core C; C. Walker, PI) will deploy cutting-edge assays for the elucidation of T-cell function, and provide a unique resource among the Wellstone network. The Education Core (Core D; P. Martin, PI) will build upon nationally recognized graduate and post-graduate programs to provide a unique educational environment.

描述（由申请人提供）：现在进入临床试验的潜在疗法治疗Duchenne肌营养不良症包括微肺炎基因转移（导致内部截短的肌营养不良蛋白）和抑制无义突变（导致全长肌营养不良蛋白）。在最近完成的每个人的试验中，我们已经确定了针对治疗和未治疗患者的肌营养不良蛋白表位的明显的T细胞免疫反应。这是我们井石肌肉营养不良合作研究中心的总体目标，旨在确定这种免疫力的患病率和分子决定因素，并确定对肌营养不良蛋白和重组AAV的作用在基因矫正疗法的成功或失败中可能发挥的作用。为了实现这一目标，我们提出了一项计划，该计划利用基因治疗中心的广泛专业知识和资源，用于NCH的疫苗和免疫力。在项目1（J. R.Mendell，PI）中，我们将表征DMD受试者中肌营养不良蛋白特异性T细胞的特性和患病率；确定糖皮质激素治疗开始调节这种反应的影响；并在AAV8.MCK.Micro-Dystrophin的血管递送的试验试验中评估这些反应。在项目2（PI C. Walker）中，我们将通过短暂的血清中和抗体来评估AAV-免疫个体中转基因递送的增强；定义CD4-II和/或CD8+ T细胞对外国转基因产物的作用，在清除RAAV转移的肌细胞中的作用；并确定T细胞激活和扩张的瞬态阻滞是否有助于非自发转基因的持续表达。行政核心（核心A; J. Mendell，pi）利用具有管理DMD协作试验和项目经验的员工，包括基因治疗的首次人工试验。组织病理学核心（Core C; Z. Sahenk，PI）将利用专家人员提供资源来分析该和其他Weilstone中心内的项目。免疫学科学核心（Core C; C. Walker，PI）将部署尖端的测定法以阐明T细胞功能，并在Wellstone网络中提供独特的资源。教育核心（核心D; P. Martin，PI）将建立在全国认可的研究生和研究生课程的基础上，以提供独特的教育环境。