PREVENTION OF ATHEROSCLEROSIS BY GENE TRANSFER

Coronary artery disease (CAD) due to atherosclerosis is the
leading cause of death and disability in our society. Plasma HDL
cholesterol is the best available biochemical predictor of CAD.
Low HDL levels are correlated with an increased incidence of
premature CAD and high HDL levels are thought to be protective.
Apolipoprotein Al (Apo Al) is the major protein constituent of
HDL particles. Infusion of Apo Al into animals leads to an
elevation in plasma levels of HDL. The timecourse for
development of atherosclerosis makes it impractical to administer
Apo Al by infusion however. We propose to use gene transfer
techniques to test whether mice predisposed to atherosclerosis
can be protected by over-expressing the gene for human Apo Al.
One of the most common and easily available inbred strains of
mice, C57/BL6, is the ideal model for our studies. We have
already demonstrated in tissue culture that mouse fibroblasts
transfected with an Apo Al expression vector produce HDL. We
have also developed the capacity to produce lines of transgenic
mice. We now propose to construct additional Apo Al expression
vectors based on viral promoters and test these vectors in
fibroblast and hepatoma cells. The viral promoter-Apo Al fusion
genes will subsequently be used to produce lines of transgenic
mice that express high levels of Apo Al. Mice that express high
levels of HDL will be assayed for their resistance to
atherosclerosis.