ADENO-ASSOCIATED VIRUS VECTORS FOR CYSTIC FIBROSIS GENE THERAPY

用于囊性纤维化基因治疗的腺相关病毒载体

• 批准号: 6242301
• 负责人: Terence R. Flotte
• 金额: $ 13.57万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6242301
• 关键词: Adenoviridae; Macaca mulatta; adeno associated virus group; biological models; bronchoscopy; chloride channels; clinical trials; cystic fibrosis; drug adverse effect; gene expression; gene therapy; human subject; human therapy evaluation; ion transport; nonhuman therapy evaluation; recombinant proteins; respiratory disorder chemotherapy; respiratory epithelium; respiratory pharmacology; respiratory virus; transfection /expression vector

Cystic fibrosis (CF) lung disease is caused by a single gene defect which leads sequentially over years to abnormal epithelial electrolyte transport, viscous mucus secretions, obstruction of the small airways, infection, inflammation, pulmonary fibrosis, respiratory failure and death. Current approaches to gene therapy utilize a transient non- integrating virus, adenovirus, administered to adult CF patients, after irreversible lung injury has occurred. We have developed an alternative vector system, based on adeno-associated virus (AAV), a nonpathogenic human isolate which integrates stably with high efficiency into the genome of respiratory epithelial cells, both in vivo and in vitro. This type of vector might be used for stable correction of the gene defect early in life, prior to onset of irreversible lung disease. We propose to test AAV vector safety and efficacy in nonhuman primates. Clinical studies will then test the hypotheses that l) AAV-CF gene vector administration will result in recombinant CFTR protein expression and correction of airway epithelial electrolyte transport in adult CF patients, at a vector dose which results in minimal or no toxicity, and 2) that the duration of AAV- CFTR vector expression will be longer than that observed with adeno-CFTR vectors. It is hoped that these trials will lay the groundwork for long- term stable correction of the CF defect in the lungs of younger CF patients, and thereby extend and improve the quality of their lives.

囊性纤维化（CF）肺疾病是由单个基因缺陷引起的，该缺陷 多年来依次导致异常上皮电解质 运输，粘性粘液分泌物，小气道阻塞， 感染，炎症，肺纤维化，呼吸衰竭和 死亡。当前的基因治疗方法利用了瞬态非 - 整合病毒，腺病毒，在成年CF患者中施用 发生了不可逆的肺损伤。我们已经开发了一个替代方案 基于腺相关病毒（AAV）的矢量系统，一种非致病性 人分离株可稳定地融合到基因组中 体内和体外的呼吸性上皮细胞。这类 向量可以用于稳定校正基因缺陷的早期 生命，在不可逆的肺部疾病发作之前。我们建议测试AAV 非人类灵长类动物的矢量安全性和功效。临床研究将 然后测试l）AAV-CF基因载体的假设将 导致重组CFTR蛋白表达和气道校正 成人CF患者的上皮电解质转运，载体剂量 这导致最小或无毒性，以及2）AAV-的持续时间 CFTR矢量表达将比adeno-CFTR观察到的更长 向量。希望这些试验能为长期奠定基础 年轻CF肺中CF缺陷的术语稳定校正 患者，从而扩大和改善他们的生活质量。