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Ann Thorac Surg 2001;71:1823-1824
© 2001 The Society of Thoracic Surgeons
a Thoracic Oncology Section, Surgery Branch, National Cancer Institute, 10 Center Dr, Room 2B07, Bethesda, MD 20892-1502, USA
e-mail: david_schrump{at}nih.gov
Delivery of therapeutic agents via intratracheal administration is an attractive strategy for the treatment and prevention of aerodigestive tract cancers, as well as the prevention of ischemia-reperfusion injury and acute rejection following lung transplantation. Relative to viral delivery systems, naked plasmid vectors are markedly less efficient with regard to gene transfer to respiratory epithelia. However, plasmid vectors are easier and less costly to produce in large quantity, and are significantly less immunogenic than viral vectors; hence naked plasmid vectors may be utilized for repeated administration. Although presently not applicable for gene therapy of pulmonary neoplasms, naked plasma vectors expressing cytokines which function by paracrine mechanisms may be effective in attenuating the inflammatory processes associated with ischemia-reperfusion, or allograft rejection within the lung.
The authors of the present study have extensive experience in clinical pulmonary transplantation. These individuals have previously demonstrated direct gene transfer of heat shock protein-70 or nitric oxide synthetase can reduce ischemia-reperfusion, and have reported that transfection of naked plasmid expressing TGF-ß1 reduces acute rejection in animal lung transplant models. In the present study, these investigators examined the transfection efficiency of two plasmid vectors administered simultaneously prior to allograft harvest, and ascertained the effects of cold preservation on reporter gene expression following transplantation. The data indicated that naked plasmid vectors expressing multiple gene products could be delivered via intratracheal administration. Not surprisingly, exposure duration enhanced transfection efficiency. Cold ischemia diminished the transfection efficiency of naked plasmid vectors; however, if pulmonary harvest was delayed to enable uptake and transport of plasmid DNA to the nucleus, cold ischemia did not appear to diminish reporter gene expression following transplantation.
The nonhomogeneous distribution of plasmid vectors within the lung may be related to the animal model as well as the technique used for intratracheal administration in this study. Recent advances in aerosolization techniques now enable efficient, uniform intrapulmonary delivery of a variety of cytotoxic chemotherapeutic agents, antibiotics, as well as cytokines. These techniques have been sufficiently refined for the delivery of plasmid and antisense oligonucleotides to respiratory epithelium. In all likelihood, utilization of these techniques would have resulted in more uniform distribution of plasmid vectors within the lung, particularly if evaluated in the context of a large animal model in which aerosolized drug delivery is more efficient.
Clinical trials evaluating aerosolized administration of cytotoxic agents for the treatment of inoperable pulmonary neoplasms are currently underway at the National Cancer Institute as well as several other centers within the United States; in all likelihood, these preliminary trials will provide the basis for aerosolized delivery of a large variety of agents for the treatment and prevention of aerodigestive tract cancers. The delivery of cytokines which can ameliorate acute ischemia-reperfusion injury, or allograft rejection may be additional applications of aerosolization technology. Once properly formulated, aerosolized pharmacologic agents or oligonucleotides may prove to be far more efficacious than gene constructs delivered via naked plasmid, or viral vectors to respiratory epithelium. As with plasmid or viral delivery systems, the distribution of aerosolized drugs will depend on the severity of ventilatory abnormalities resulting from secretions and air trapping within the transplanted lung. Because these agents traffic across respiratory epithelium to interstitial lymphatics, drugs delivered via aerosolization techniques may simultaneously inhibit inflammatory processes occurring within the alveolar space, interstitium, and regional lymph nodes.
Doctor D’Ovidio and colleagues have confirmed that gene transfer to the respiratory epithelium is inefficient, and influenced by cold preservation techniques. Their experiments are a step in the right direction, and demonstrate the future potential of local delivery of therapeutic agents for the prevention of ischemia-reperfusion and allograft rejection in clinical lung transplantation.
Related Article
Ann. Thorac. Surg. 2001 71: 1817-1823.
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