SAFETY AND EFFICACY OF RECOMBINANT ADENOVIRUS IN THE HUMAN LUNG

重组腺病毒在人肺中的安全性和有效性

• 批准号: 6239191
• 负责人: CYNTHIA B ROBINSON
• 金额: $ 14.18万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6239191
• 关键词: Adenoviridae; chloride channels; clinical trials; cystic fibrosis; cytotoxic T lymphocyte; gene expression; gene therapy; human subject; human therapy evaluation; in situ hybridization; inflammation; ion transport; laboratory mouse; leukocyte activation /transformation; polymerase chain reaction; recombinant DNA; recombinant proteins; respiratory epithelium; tissue /cell culture

Tremendous progress has been made in the development of lung-directed gene therapy for cystic fibrosis (CF) using recombinant adenoviruses. Preclinical experiments and a variety of animal models have been instrumental in developing this technology and evaluating its potential efficacy and safety. Despite tremendous efforts by multiple groups in animal models, several critical issues remain regarding the feasibility of recombinant adenoviral technology for treatment of CF in humans. The improved recombinant adenoviruses developed and tested in Projects I and II will be used in pilot human experiments described in this component of the SCOR. Phase I clinical trials using first generation adenoviruses are underway at the University of Pennsylvania and in collaboration with investigators at the University of North Carolina. The protocol developed at Penn is based on lung-directed gene transfer, while the protocol at UNC has focused on characterizing the feasibility of gene therapy using nasal epithelial as a target. Both trials have been initiated and should be completed before this grant begins. In these initial trials we hope to establish a therapeutic index for first generation viruses as well as to characterize the duration of recombinant gene expression following a single administration of virus. This application is based on the hypothesis that cellular immune responses to genetically modified human airway epithelial cells in vivo will narrow the therapeutic index and limit the stability of genetic correction when using first generation viruses. Second generation recombinant viruses developed in Project I, and evaluated in both Project II and the Animal Models Core, will be used in new human pilot experiments described in this grant. Initial characterization of improved recombinant adenoviruses will utilize a protocol in which virus is targeted to both lung and nose. Safety, biological efficacy, and immunologic responses will be characterized in recipients. The most promising recombinant adenovirus will be characterized in another protocol designed to evaluate the feasibility of repeated administration. We will incorporate into these clinical protocols surrogate endpoints to better predict clinical efficacy based on the knowledge gained in Project II.

在肺导向的发展中取得了巨大进步 使用重组腺病毒的囊性纤维化基因治疗（CF）。 临床前实验和多种动物模型已经 有助于开发这项技术并评估其潜力 功效和安全性。 尽管有多个小组的巨大努力 动物模型，有关可行性仍然存在的几个关键问题 重组腺病毒技术用于治疗人类CF。 这 改进的重组腺病毒在项目I和 II将用于该组件中描述的试验人类实验 SCOR。 使用第一代腺病毒的I期临床试验 正在宾夕法尼亚大学进行，并与 北卡罗来纳大学的调查人员。 协议 在Penn开发的是基于肺导向基因转移，而 UNC的协议重点是表征基因的可行性 使用鼻上皮作为靶标的治疗。 这两个试验都是 启动并应在这笔赠款开始之前完成。 在这些 初步试验，我们希望为首先建立一个治疗指数 发电病毒以及重组持续时间 单个病毒给药后的基因表达。 这 应用基于以下假设 转基修饰的人体气道上皮细胞体内会狭窄 治疗指数并限制遗传校正的稳定性 使用第一代病毒。第二代重组病毒 在项目I中开发，并在项目II和动物中进行了评估 模型核心将用于新的人类飞行员实验中 这笔赠款。 改进的重组的初始表征 腺病毒将利用病毒针对两者的方案 肺和鼻子。 安全性，生物学功效和免疫反应 将以接收者为特征。 最有希望的重组 腺病毒将在另一个旨在评估的协议中进行表征 重复给药的可行性。 我们将纳入 这些临床方案替代终点以更好地预测临床 基于项目II中获得的知识的功效。