PPG-GENE THERAPY FOR CYSTIC FIBROSIS LUNG DISEASE

PPG 基因治疗囊性纤维化肺病

• 批准号: 6885336
• 负责人: MICHAEL J. WELSH
• 金额: $ 178.66万
• 依托单位: UNIVERSITY OF IOWA
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6885336
• 关键词: clinical research; cystic fibrosis; gene therapy; human tissue; lung disorder; transfection /expression vector

DESCRIPTION (provided by applicant): Gene transfer to the airways of patients with cystic fibrosis (CF) could represent a major therapeutic advance for this lethal disease. Although previous work in vitro, in animals and in people with CF has established the feasibility of gene transfer, it has also revealed the limitations of current approaches. The two greatest barriers are limited efficiency of gene transfer from the apical surface of differentiated airway epithelia and limited persistence of expression. The projects in this program utilize novel approaches and models to overcome these barriers. Recent work showed that adeno-associated viruses-5 (AAV5) vectors target the apical surface of differentiated airway epithelia, which makes them an attractive vector. Project by Welsh (subproject 0001) focuses on overcoming the limited packaging capacity of AAV vectors and will test the long-term potential of AAV5 vectors to correct the CF C1- transport defect. In Project by Zabner (subproject 0004), the investigators will study how AAV5 interacts with its apical membrane receptors, sialic acid and PDGF-receptor. They combine this with a structural analysis of the virus and its receptor. Project by McCray (subproject 0005) takes a related approach to achieving apical targeting and long-lasting expression by developing LCMV-pseudotyped lentivirus vectors. They investigate the virus:receptor interactions and will test the ability to achieve persistent expression in airway epithelia. Our ability to answer several crucial questions about gene transfer has been hampered by the lack of an animal model that faithfully reproduces the lung disease found in humans with CF. Project by Welsh (subproject 0006) addresses this problem by developing a porcine model of CF. The PPG benefits from outstanding support by the In Vitro Models and Cell Culture Core, the Gene Transfer Vector Core, and the Administrative Core. These studies will take us closer to our long-term goal of developing new therapies for people who suffer from CF.

描述（由申请人提供）： 将基因转移到囊性纤维化（CF）患者气道可能代表这种致命疾病的重大治疗进展。 尽管之前在体外、动物和患有囊性纤维化的人身上进行的研究已经证实了基因转移的可行性，但它也揭示了当前方法的局限性。两个最大的障碍是从分化的气道上皮细胞顶端表面转移基因的效率有限和表达的持久性有限。 该计划中的项目利用新颖的方法和模型来克服这些障碍。 最近的研究表明，腺相关病毒 5 (AAV5) 载体靶向分化的气道上皮细胞的顶端表面，这使它们成为一种有吸引力的载体。 Welsh的项目（子项目0001）专注于克服AAV载体的有限包装能力，并将测试AAV5载体纠正CF C1-运输缺陷的长期潜力。 在 Zabner 的项目（子项目 0004）中，研究人员将研究 AAV5 如何与其顶膜受体、唾液酸和 PDGF 受体相互作用。 他们将其与病毒及其受体的结构分析结合起来。 McCray 的项目（子项目 0005）采用了相关方法，通过开发 LCMV 假型慢病毒载体来实现顶端靶向和持久表达。 他们研究了病毒：受体的相互作用，并将测试在气道上皮细胞中实现持续表达的能力。 由于缺乏能够忠实再现 CF 人类肺部疾病的动物模型，我们回答有关基因转移的几个关键问题的能力受到了阻碍。 威尔士的项目（子项目 0006）通过开发 CF 猪模型解决了这个问题。 PPG 受益于体外模型和细胞培养核心、基因转移载体核心和管理核心的出色支持。 这些研究将使我们更接近为 CF 患者开发新疗法的长期目标。