DESCRIPTION: The broad, long-term objective is to cure diet-induced atherosclerosis by raising the levels of HDL-C (high density lipoprotein cholesterol) using gene therapy. HDL protects against atherosclerosis, but methods to increase HDL levels are inadequate to prevent disease in many people. This proposal suggests a new means to treat coronary heart disease. Gene constructs producing apolipoprotein (apo) A-I transplanted into marrow precursor cells would elevate HDL-C, since apoA-I is an HDL component present in limiting amounts. Gene constructs successful in mice would be tested in other animals and in human beings. Amounts of apo A-I are maximized by using the most effective promoters and marrow grafting methods. Specific aims test the following hypotheses: (1) That certain promoters drive high levels of apo A-I production by marrow derived cells. Promoter-apo A-I gene constructs leading to high apo A-I and HDL production by marrow-derived cells will be screened in marrow- derived cells and used to make transgenic mice, whose marrow will be grafted into recipients to test if HDL-C levels are increased. Promoters driving strong gene expression generally and those specific for marrow cell descendants will be compared. (2) That marrow grafts with promoter-apo A-I gene constructs protect from atherosclerosis. Recipients will be given low doses of irradiation after drug pretreatment to allow repopulation with minimum damage. Transgenic marrow grafts raising HDL-C levels from Aim I will be tested for the ability to protect B6 mice fed an atherogenic diet and atherosclerosis- susceptible mutants. The minimum amounts of gene-transplanted marrow required will be determined. (3) That increased levels of HDL-C cause atherosclerotic plaques to regress. Lesions regress in the mouse in initial studies, with a rise in HDL-C. Plaques will be defined in detail as they develop and regress. Then the degree of regression will be related to plasma HDL levels. Finally, regression will be characterized in normal and mutant recipients of the most effective transgenic marrow grafts.