Gene and Pharmacological Therapies for Cystic Fibrosis

本中心的总体目标是利用我们现有的CF研究小组在基础和临床研究以及患者护理方面的优势，开发CF患者的基因和药物治疗方法。具体目标是开发腺相关病毒载体作为基因治疗药物，并探索基于改变突变CFTR的表达和运输的新的药物治疗方法。项目1将基于AAV5血清型开发一种新的AAV基因治疗载体，作为CF的一种新疗法。目的是：评估载体DNA转移的效率和分布，确定免疫反应、肺功能改变或在猴子远处器官扩散的风险。随后将在成人CF患者中进行临床试验。项目二：CF基因治疗的腺相关病毒载体。需要验证的主要假设是：某些抗蛋白酶、抗炎和糖基化相关基因的异常下调与CF肺病有关，而这些物质的增加将改善CF肺病的表型。项目三：苯丁酸治疗CF是基于假设苯丁酸可以部分纠正CF患者鼻电位差缺陷。目的是准确地查明苯丁酸盐是如何部分恢复运输功能的。项目四将侧重于AAV的生物学。最后，有三个核心，一个表达式，一个矢量核心和一个管理核心。

It is overall goal of this Center to utilize the strengths of our current CF Research Group in basic and clinical research and patient care to develop gene and pharmacologic therapies for patients with CF. The specific aims are to develop adeno-associated viral vectors as gene therapy agents and to explore new pharmacologic therapies based upon altering expression and trafficking of mutant CFTR. Project 1 will develop a new AAV gene therapy vector based on the AAV5 serotype as a new therapy for CF. The aims will be to: assess the efficiency and distribution of vector DNA transfer and to determine the risk of immunologic reactions, alterations in pulmonary function, or spread in distant organs in monkeys. This will be followed by a clinical trial in adult CF patients. Project II: Adeno-associated virus vectors for CF gene therapy. The primary hypotheses to be tested ti that: Aberrant down-regulation of certain anti-protease, anti-inflammatory, and glycosylation-related genes contribute to CF lung disease, and augmentation of these substances will ameliorate the CF lung disease phenotype. Project III: Phenylbutyrate Therapy for CF is based on the hypothesis that phenylbutyrate can act to partially correct defective nasal potential difference in CF patients. The goals are to pinpoint exactly how phenylbutyrate functions to partially restore transport function. Project IV will focus on the Biology of AAV. Finally, there are three cores, an Expression, a Vector Core, and an Administration Core.