Overcoming Immune Barriers to Gene Correction for Duchenne Muscular Dystrophy

描述（由申请人提供）：目前进入治疗杜氏肌营养不良临床试验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）。在最近完成的人体试验中，我们已经在治疗和未治疗的患者中发现了针对肌营养不良蛋白表位的显著t细胞免疫反应。我们的Wellstone肌肉萎缩症合作研究中心的总体目标是确定这种免疫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的免疫反应在基因校正治疗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，利用NCH基因治疗中心和疫苗与免疫中心的广泛专业知识和资源。在项目1 （j.r.m endell， PI）中，我们将描述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；确定开始糖皮质激素治疗对调节这种反应的影响；并在血管输送aav8 . mck .微营养不良蛋白的中试试验中评估这些反应。在项目2 （C. Walker， PI）中，我们将通过短暂耗尽血清中和抗体来评估转基因在aav免疫个体中的传递增强；明确CD4-I和/或CD8+ T细胞在清除raav转导的肌细胞中对抗外源转基因产物的作用；并确定T细胞激活和扩增的短暂阻断是否有助于非自体转基因的持续表达。行政核心（核心A； J. Mendell， PI）利用具有管理DMD合作试验和项目经验的骨干人员，包括基因治疗的首次人体试验。组织病理学核心（核心C； Z. Sahenk， PI）将利用专家人员为本中心和其他威尔斯通中心项目的组织分析提供资源。免疫学科学核心（核心C； C. Walker， PI）将部署尖端的分析来阐明t细胞的功能，并在Wellstone网络中提供独特的资源。教育核心（核心D； P. Martin， PI）将以国家认可的研究生和研究生课程为基础，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.