Gene therapy for acute lung injury

Citation
Kl. Brigham et Aa. Stecenko, Gene therapy for acute lung injury, INTEN CAR M, 26, 2000, pp. S119-S123
Citations number
9
Categorie Soggetti
Aneshtesia & Intensive Care
Journal title
INTENSIVE CARE MEDICINE
ISSN journal
03424642 → ACNP
Volume
26
Year of publication
2000
Supplement
1
Pages
S119 - S123
Database
ISI
SICI code
0342-4642(2000)26:<S119:GTFALI>2.0.ZU;2-B
Abstract
The remarkable transition of biological science into the age of molecular b iology held great promise for development of new therapies for treatment of human disease. The fact that exists for analyzing genetic material in exqu isite detail and constructing DNA in virtually any desired form was the bas is for promising rapid translation into clinical medicine and the final cur e 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 f rame which was expected. That result is neither because the rationale was f aulty nor because the tools of molecular biology were wanting. The devil wa s 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 th eoretical and practical problems. In the lungs, these vectors have not fulf illed their original promise. Non-viral based strategies work in a general sense, but efficiency of gene delivery in vivo has been a limitation. In ad dition, the experimental end points in both clinical and preclinical invest igation have been most often designed to demonstrate phenomenology rather t han potential efficacy And, why limit the potential of gene therapy to inhe rited disease? In fact, treatment of acquired diseases by increasing or dec reasing expression of a given gene in the lungs that would hasten recovery from an acquired disease might be easier than treating inherited disease be cause the requirements for duration of transgene expression would be less s tringent. Over the past two decades, we have learned enough about the patho genesis of acute lung injury to predict that increased (or decreased) produ ction 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 stra tegies 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 constitut ive form of the cyclooxygenase gene (COX-1) results in increased production of prostacyclin and PGE(2) by the lungs and inhibits endotoxin induced pul monary hypertension and edema. Additional studies demonstrate that increase d expression of the alpha-1 antitrypsin gene in human respiratory epitheliu m 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 evide nce to date indicates that current technology is sufficiently robust to pur sue this novel area for treatment of this devastating disease.