The goal of this PPG, Gene Therapy for Pulmonary and Hematologic Disorders, is to facilitate translation of basic knowledge of gene delivery to safe and rigorous human clinical trials. The long-range goal is to provide novel therapeutic modalities for treating monogenetic diseases such as Hemophilia and Cystic Fibrosis. The major objectives in the UNC PPG are: (1) the development of highly efficient and high titer viral vectors, optimum expression, and safe persisting delivery systems, and (2) development of novel animal models for better defining rate limiting steps involved in target cell transduction, analysis of long term high level vector gene expression, and expression of normal and mutant human genes (e.g. FIX, CFTR). Four basic science projects and four cores are proposed. The basic research projects are proposed to focus on understanding rate-limiting steps in effective gene transfer. Projects 1 and 2 focus on AAV (Samulski) and Lentivirus (Olsen and Kafri), respectively. These projects are aimed at understanding and overcoming inefficient gene delivery related to virus entry and persistent transgene expression. The goal of the proposed studies is to generate new knowledge about the safety and biological efficacy of gene delivery, which will provide information important to the design of future clinical trials. Projects 3 and 4 involve animal models for airway (Boucher) and hemophilia (Stafford) disorders, respectively. These studies aim to define the host-associated rate limiting step(s) for understanding of the cell biology of the target tissue for efficient in vivo gene delivery and translating improvements in vector development. Specifically, goals include increasing access to airway epithelia (Project 3), development of novel models (e.g. a humanized hemophilia mouse, Project 4). This work will be supported by four cores, Administrative (Core A), Vector (Core B), Animal (Core C), and Morphology (Core D). The PPG is a highly interactive program comprised of clinical investigators and expert basic laboratories designed to optimize vectors and to test their interactions with target cells in vitro and in vivo. The ultimate goal of the UNC PPG is to achieve safe, effective, gene delivery in humans.
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