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.