Researchers at Baylor College of Medicine have improved amethod of delivering genes to liver cells in a system that mightone day facilitate using DNA to treat metabolic disorders.
Led by Savio Woo, the research team in Houston created 1,000times the previous amount of an easily visualized "marker"gene product, beta galactosidase, by hitching the gene to anadenovirus.
Adenoviruses cause the common cold and have attractedinterest as a vehicle to introduce genes to cells for genetherapy.
At Baylor, however, Woo's group already targeted the liver byincluding a glycoprotein that is taken up by liver receptorsinvolved in removing aging proteins from blood plasma.
Previous studies without the adenovirus component resulted inless than one-tenth of 1 percent of the liver cells receivingwhole copies of the gene, because the glycoprotein was shunteddirectly to a cellular wrecking facility, the lysosome, thatdismantles old components.
Adenoviruses infect cells by escaping the balloon-likeendosomes that transport components to lysosomes fordismantling, a feat that Woo capitalized on in his gene-transfersystem.
He tested the system in mouse cells, grown in culture, thatmimic phenylketonuria (PKU), a metabolic disorder that causessevere mental retardation in children. Mouse cells that couldnot previously break down phenylalanine took up the humanphenylalanine hydroxylase gene and began to properly processthis amino acid.
This method shows "great promise" for efficiently deliveringgenes to correct liver disorders, Woo and his collaboratorswrote in a report on their research published in the Marchissue of the Proceedings of the National Academy of Sciences.
The group has started testing the system in mice. Once thetechnology is developed, dozens of metabolic disorders causedby deficient genes in the liver might be addressed, Woo toldBioWorld, including augmenting removal of "bad" cholesterol inthe liver by fixing genetically impaired low-density lipoproteinreceptors.
"When we see a high level of expression in the mouse," Woosaid, "we will try to apply for clinical trials in patients."Although the academic team would probably carry out initialclinical trials as primary investigators, later development mightinvolve joint efforts with a commercial partner.
Woo has constructed self-contained rings of DNA calledplasmids to introduce genes into the liver. Other groupsworking in gene transfer in the lung and brain have insteadincorporated foreign genes into the adenovirus. For safety, thegroups use a replication-deficient virus that cannot grow. Wooenvisions eventually doing away with the virus entirely,retaining just the parts of the viral DNA necessary to escapebreakdown in the lysosome.
-- Nancy Garcia Associate Editor
(c) 1997 American Health Consultants. All rights reserved.