Basis of Pulmonary Toxicity Associated with Cationic Lipid-Mediated Gene Transfer to the Mammalian Lung

作者：Ronald K. Scheule, Judith A. St. George, Rebecca G. Bagley, John Marshall, Johanne M Kaplan, Geoffrey Y. Akita, Kathryn X. Wang, Edward R. Lee, David James Harris, Canwen Jiang, Nelson S. Yew, Alan E. Smith, Seng H. Cheng · 发表于：Human Gene Therapy · 年份：1997 · DOI：10.1089/hum.1997.8.6-689 · 被引用次数：251 · 研究领域：RNA Interference and Gene Delivery、Virus-based gene therapy research、Advanced biosensing and bioanalysis techniques

Studies have indicated that although abundant levels of transgene expression could be achieved in the lungs of mice instilled with cationic lipid:pDNA complexes, the efficiency of gene transfer is low. As a consequence, a relatively large amount of the complex will need to be administered to the human lungs to achieve therapeutic efficacy for indications such as cystic fibrosis. Because all cationic lipids exhibit some level of cytotoxicity in vitro, we assessed the safety profile of one such cationic lipid, GL-67, following administration into the lungs of BALB/c mice. Dose-dependent pulmonary inflammation was observed that was characterized by infiltrates of neutrophils, and, to a lesser extent, macrophages and lymphocytes. The lesions in the lung were multifocal in nature and were manifested primarily at the junction of the terminal bronchioles and alveolar ducts. The degree of inflammation abated with time and there were no apparent permanent fibrotic lesions, even in animals that were treated at the highest doses. Analysis of the individual components of the complex revealed that the pulmonary inflammation was primarily cationic lipid-mediated with a minor contribution from the neutral co-lipid DOPE. Associated with the lesions in the lungs were elevated levels of the pro-inflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) that peaked at days 1–2 post-instillation but resolved to normal limits by day 14. Total cell count...