Overcoming Immune Barriers to Gene Correction for Duchenne Muscular Dystrophy

描述(申请人提供)：目前进入临床试验的治疗Duchenne肌营养不良症的潜在疗法包括微肌营养不良蛋白基因转移(导致内部截断的dystrophin)和抑制无义突变(导致全长dystrophin)。在最近完成的每一项人体试验中，我们都发现了针对Dstrophin表位的显著T细胞免疫反应，无论是在接受治疗的患者还是未治疗的患者中。我们韦尔斯通肌肉营养不良合作研究中心的总体目标是确定这种免疫的流行率和分子决定因素，并确定对抗肌营养不良蛋白和重组AAV的免疫反应在基因纠正疗法的成败中可能发挥的作用。为了追求这一目标，我们提出了一项计划，该计划利用了NCH基因治疗中心和疫苗和免疫中心的广泛专业知识和资源。在项目1(J.R.Mendell，PI)中，我们将描述DMD受试者中Dstrophin特异性T细胞的特性和流行率；确定糖皮质激素治疗开始对调节这一反应的影响；并在AAV8.MCK.Micro-dystrophin血管输送的试点试验中评估这些反应。在项目2(C.Walker，Pi)中，我们将评估通过瞬时耗尽血清中和抗体来增强AAV免疫者的转基因传递；确定针对外源转基因产物的CD4-I和/或CD8+T细胞在清除rAAV转导的心肌细胞中的作用；以及确定瞬时阻断T细胞的激活和扩张是否有助于非自身转基因的持续表达。管理核心(核心A；J·门德尔，PI)利用了一批在管理DMD合作试验和项目方面有经验的工作人员，包括基因治疗的第一人试验。组织病理学核心(核心C；Z.Sahenk，PI)将利用专家工作人员为本中心和其他魏尔斯通中心内项目的组织分析提供资源。免疫学科学核心中心(Core C；C.Walker，PI)将部署用于阐明T细胞功能的尖端分析，并在韦尔斯通网络中提供独特的资源。教育核心(核心D；P.Martin，PI)将建立在国家认可的毕业生和研究生课程的基础上，以提供独特的教育环境。

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.