GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS

自从克隆了Cf基因以来，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 Cftr的数量大大增加。几种新的令人兴奋的潜在疗法 基于对CFR的一般知识，特别是CFTR，已经 已开发的，包括基于基因和药物疗法。它 本中心的总体目标是利用我们的优势 目前在基础和临床研究和患者方面的CF研究小组 关注为CF患者开发基因和药物治疗。 其具体目标是发展腺相关病毒载体作为基因 治疗药物和探索新的药物治疗方法 改变突变的cftr的表达和运输。第一个项目 将解决重复递送腺相关病毒的问题 向量。目的将评估效率和分配 载体DNA转移和确定免疫反应的风险， 肺功能的改变，或扩散到远处的器官 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旨在 明确和克服纤维蛋白原呼吸道转运障碍 患者通过AAV和开发更多有效的AAV载体。丁酸苯酯 能部分矫正CF的鼻电位差缺陷 病人。目标是准确地确定丁酸苯酯是如何发挥作用的。 以部分恢复运输功能并鉴定丁酸盐- 敏感序列。项目IV将侧重于AAV的生物学。这个 目标是详细研究倒置终端的哪些组件 重复序列作为复制的起点，分离RNA AAV DNA复制所需的复制酶，以及识别 与AAV rep蛋白相互作用的细胞酶。最后，还有 三个核心：表达核心、载体核心和管理核心 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.