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==== Front Intensive Care Med Intensive Care Med Intensive Care Medicine 0342-4642 1432-1238 Springer-Verlag Berlin/Heidelberg 10786968 0026S119.134 10.1007/s001340051128 Article Gene therapy for acute lung injury Brigham K. L. Stecenko A. A. grid.152326.10000000122647217Center for Lung Research, Vanderbilt University School of Medicine, Nashville, Tennessee, USA 37232 Tel.:(615) 322–3412 Fax: (6 15) 343–7448, , , , US 2000 26 Suppl 1 S119 S123 © Springer-Verlag Berlin Heidelberg 2000This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic. The remarkable transition of biological science into the age of molecular biology held great promise for development of new therapies for treatment of human disease. The fact that the technology exists for analyzing genetic material in exquisite detail and constructing DNA in virtually any desired form was the basis for promising rapid translation into clinical medicine and the final cure for genetically determined diseases; cystic fibrosis is the prime example of such a lung disease. The promise was not kept, at least not in a time frame which was expected. That result is neither because the rationale was faulty nor because the tools of molecular biology were wanting. The devil was and is in the details. How do you deliver DNA to the desired cell targets in amounts sufficient to accomplish the desired effect? Viral vectors have received the most attention, but viral vectors have proven to have both theoretical and practical problems. In the lungs, these vectors have not fulfilled their original promise. Non-viral based strategies work in a general sense, but efficiency of gene delivery in vivo has been a limitation. In addition, the experimental end points in both clinical and preclinical investigation have been most often designed to demonstrate phenomenology rather than potential efficacy. And, why limit the potential of gene therapy to inherited disease?

eral sense, but efficiency of gene delivery in vivo has been a limitation. In addition, the experimental end points in both clinical and preclinical investigation have been most often designed to demonstrate phenomenology rather than potential efficacy. And, why limit the potential of gene therapy to inherited disease? In fact, treatment of acquired diseases by increasing or decreasing expression of a given gene in the lungs that would hasten recovery from an acquired disease might be easier than treating inherited disease because the requirements for duration of transgene expression would be less stringent. Over the past two decades, we have learned enough about the pathogenesis of acute lung injury to predict that increased (or decreased) production of certain biologically active mediators should be beneficial. Genes encoding some of these mediators have been cloned and constructs made which express the genes. It is now possible using either viral or non-viral strategies to deliver expression constructs to the lungs and, since acute lung injury has a dismal prognosis and no effective drugs have been identified, this seems a good clinical target for gene therapy. In preclinical studies, we have shown that increased expression of the gene encoding the constitutive form of the cyclooxygenase gene (COX-1) results in increased production of prostacyclin and PGE2 by the lungs and inhibits endotoxin induced pulmonary hypertension and edema. Additional studies demonstrate that increased expression of the alpha-1 antitrypsin gene in human respiratory epithelium in culture and in vivo has anti-viral and anti-inflammatory effects that are not predicted by extracellular concentrations of the transgene product. Thus, acute lung injury is a reasonable target for gene therapy, and evidence to date indicates that current technology is sufficiently robust to pursue this novel area for treatment of this devastating disease.

d anti-inflammatory effects that are not predicted by extracellular concentrations of the transgene product. Thus, acute lung injury is a reasonable target for gene therapy, and evidence to date indicates that current technology is sufficiently robust to pursue this novel area for treatment of this devastating disease. Keywords Cystic FibrosisGene TherapyPulmonary HypertensionPGE2Acute Lung Injuryissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2000