GENE AND PHARMACOLOGICAL THERAPIES FOR CYSTIC FIBROSIS

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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.