Overcoming Immune Barriers to Gene Correction for Duchenne Muscular Dystrophy

描述（由申请人提供）：目前进入杜氏肌营养不良症临床试验的潜在治疗方法包括微肌营养不良蛋白基因转移（产生内部截短的肌营养不良蛋白）和抑制无义突变（产生全长肌营养不良蛋白）。在最近完成的每一项人体试验中，我们已经在治疗和未治疗的患者中确定了针对抗肌萎缩蛋白表位的显著T细胞免疫应答。我们的Wellstone肌营养不良合作研究中心的总体目标是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的免疫应答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，我们将表征DMD受试者中肌养蛋白特异性T细胞的性质和流行率;确定糖皮质激素治疗的开始对调节该应答的影响;并在AAV8.MCK.微肌养蛋白的血管递送的先导试验中评估这些应答。在项目2（C.步行者，PI），我们将评估通过血清中和抗体的瞬时消耗增强AAV免疫个体中的转基因递送;定义CD 4 - 1-和/或CD 8 + T细胞针对外源转基因产物在清除rAAV转导的肌细胞中的作用;并确定T细胞活化和扩增的瞬时阻断是否促进非自身转基因的持续表达。管理核心（核心A; J. Mendell，PI）利用具有管理DMD合作试验和项目经验的工作人员骨干，包括基因治疗的首次人体试验。历史学核心（Core C; Z。Sahenk，PI）将利用专家工作人员为该中心和其他Weilstone中心的项目提供组织分析资源。免疫学科学核心（Core C; C。步行者，PI）将部署尖端的分析，阐明T细胞的功能，并提供一个独特的资源之间的井石网络。教育核心（核心D; P.马丁，PI）将建立在国家认可的研究生和研究生课程，以提供一个独特的教育环境。

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.