GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS

自从克隆了CF基因，我们对遗传学的理解 生物学、生理学和病理生理学、生物化学和细胞生物学 的CFTR大大增加。几种新的令人兴奋的潜在疗法 基于CF的一般知识，特别是CFTR， 包括基因疗法和药物疗法。它 是本中心的总体目标，利用我们的优势， 目前CF研究小组在基础和临床研究和患者 关心开发基因和药物治疗CF患者。 其具体目标是开发腺相关病毒载体， 治疗药物和探索新的药理学疗法的基础上， 改变突变CFTR的表达和运输。第一个项目 将讨论腺相关病毒的重复递送问题 向量。其目的是评估以下方面的效率和分布情况： 载体DNA转移和确定免疫反应的风险， 肺功能改变，或扩散到远处器官， 猴子随后将在成人CF患者中进行临床试验。 用于CF基因治疗的腺相关病毒载体被设计成 确定并克服CF气道传导障碍 患者的AAV和开发更有效的AAV载体。苯丁酸 可以部分纠正CF中有缺陷的鼻电位差 患者目标是精确地确定苯丁酸盐的功能 部分恢复运输功能，并确定丁酸盐- 敏感序列项目IV将侧重于AAV的生物学。的 目标是详细研究倒置终端的哪些组件 重复序列作为复制起点，分离RNA AAV DNA复制所需的复制酶，并鉴定 与AAV rep蛋白相互作用的细胞酶。最后是 三核：表达核、载体核和给药 核心

Since the cloning of the CF gene, our understanding of the genetics biology, physiology and pathophysiology, biochemistry, and cell biology of CFTR has increased greatly. Several new exciting potential therapies based on knowledge of CF in general and CFTR in particular have been developed, including both gene-based and pharmacological therapies. It is the 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 explore new pharmacologic therapies based upon altering expression and trafficking of mutant CFTR. The first project will address the question of Repeat Delivery of Adeno-associated virus vectors. The aims will be to assess the efficiency and distribution of vector DNA transfer and determine the risk of immunologic reactions, alterations in pulmonary functions, or spread in distant organs in monkeys. This will be followed by a clinical trial in adult CF patients. Adeno-associated virus vectors for CF gene therapy is designed to ascertain and overcome the barriers to transduction of airways of CF patients by AAV and to develop more potent AAV vectors. 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 and to identify butyrate- sensitive sequences. Project IV will focus on the Biology of AAV. The goals are to study in detail which components of the inverted terminal repeats function as an origin of replication, isolate the RNA replication enzymes required for AAV DNA replication and to identify the cellular enzymes that interact with AAV rep protein. Finally, there are three cores: an expression core, a vector core, and an administration core.