Non-Technical Abstract 
RAC Application 
Kenneth L. Brigham, M.D. 
Non-Technical Abstract 
NON-TECHNlCAL ABSTRACT 
When inflammation occurs in the lungs, lung cells are injured in part by the release of 
enzymes from some white blood cells which digest proteins. Normally, a protein present in the 
lungs counteracts the damaging enzymes; this protein is called alpha-1 antitrypsin (AAT). 
Some people inherit a deficiency of AAT because the gene responsible for producing it is 
defective. These patients develop emphysema at an early age, presumably because the white 
blood cell enzymes digest the lungs. Also, w hen the lungs are injured as a result of blood stream 
infection, trauma or some other causes, this, too, appears to be in part because the white blood 
cells release the same enzymes which digest lung ceils. In this case, the person may have 
normal amounts of AAT, but so much of the enzymes are released that this normal defense is 
overwhelmed. In either case (either AAT deficiency or acute lung injury), if lung cells could 
be genetically engineered to make increased amounts of AAT, the lung might be protected from 
injury. We propose to give the gene for AAT imbedded in some DNA which will cause the gene 
to make the AAT protein in large amounts to the lungs of humans. We will use DNA in a form 
which does not incorporate into host DNA (a circular form of DNA called a plasmid) and we 
will combine the plasmid with small fat globules called liposomes. These special liposomes are 
constructed so that they associate by charge interaction with DNA and escort the DNA into 
cells so that it can be expressed. In order to expose patients to minimal risk, we propose to 
begin by putting the plasmid/liposome into a lung that is going to be removed for some other 
reason (usually cancer) 2-3 days before surgery and then obtaining some of the removed lung 
at surgery in order to see whether there was any damage and also whether the gene we gave is 
working in the lungs. In some patients with AAT deficiency, we propose to give the 
plasmid/liposome to one nostril and then wash the nostrils each day to measure AAT in the 
fluid as a measure of whether the gene we gave is working. Some cells will also be taken from 
the nose by scraping and tested for the administered gene function. We have shown in cells in 
culture and in animals that the plasmid/liposome technology works and is safe; these studies 
will determine whether that is also true in the human respiratory tract. This information is 
critical to proceeding to any tests of therapeutic effectiveness of this approach. 
Recombinant DNA Research, Volume 19 
[171] 
