Gene and Pharmacological Therapies for Cystic Fibrosis

该中心的总体目标是利用我们目前CF研究组在基础和临床研究以及患者护理方面的优势，为CF患者开发基因和药物治疗。具体目标是开发腺相关病毒载体作为基因治疗剂，并探索基于改变突变CFTR的表达和运输的新的药理学疗法。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的新疗法。其目的是：评估载体DNA转移的效率和分布，并确定免疫反应、肺功能改变或在猴远端器官中扩散的风险。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。待检验的主要假设是：某些抗蛋白酶、抗炎和糖基化相关基因的异常下调有助于CF肺病，这些物质的增加将改善CF肺病表型。项目三：苯丁酸盐治疗CF是基于苯丁酸盐可以部分纠正CF患者的鼻电位差缺陷的假设。目标是精确地确定苯丁酸盐如何部分恢复运输功能。项目IV将侧重于AAV的生物学。最后，有三个核心：表达式核心、向量核心和管理核心。

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.