Atherosclerosis causes heart attacks, strokes, and peripheral vascular disease, and is a consequence of disease processes that develop within the blood vessel wall. This proposal seeks to develop gene therapy, delivered to the blood vessel wall, that prevents the biological processes that drive the progression of atherosclerosis. Eventually, by expressing anti-atherosclerotic transgenes in human vascular tissue, this approach may yield blood vessels that remain disease-free indefinitely because they are resistant to the underlying biological processes that cause atherosclerosis. This is an ambitious objective, including work that is certain to extend beyond the current proposal. However, the current proposal builds on several years of progress in the laboratory of the Principal Investigator and sets forth the next critical steps towards gene therapy for atherosclerosis. ? ? There are three specific aims. The first specific aim will test gene-therapy strategies that prevent atherosclerosis by increasing lipid transport out of the vessel wall or by decreasing vascular inflammation.
The second aim i ncludes experiments that will reveal the duration of transgene expression that can be achieved in vascular tissue using helper-dependent adenoviral vectors. Other experiments will test strategies for increasing transgene expression from these vectors.
The third aim will test the hypothesis that helper- dependent adenoviral vectors will provide durable transgene expression with minimal associated inflammation in vein grafts. Success in these aims will represent significant progress towards development of clinically useful vascular gene therapy. ? ?

Public Health Relevance

The three current therapies for atherosclerosis-drugs, angioplasty, and bypass surgery-have not eliminated death and disability associated with atherosclerosis. Patients receiving one or even all three of these therapies continue to be at risk for heart attacks, strokes, and limb loss. Development and clinical application of methods and tools to genetically engineer blood vessels so that they do not develop atherosclerosis-and therefore never become narrowed or clogged-would have a major impact on the morbidity, mortality, and health-care costs of cardiovascular disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL076226-03
Application #
7469417
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Lundberg, Martha
Project Start
2006-07-01
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
3
Fiscal Year
2008
Total Cost
$518,298
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195