Marfan syndrome is a devastating connective tissue disorder that commonly causes death due to aortic rupture or dissection in the fourth decade of life if untreated. Marfan syndrome affects 1 out of every 5,000 people, with no predisposition based on gender, race, or ethnicity. Therapeutics for Marfan-related aortopathy are limited in terms of efficacy, need for frequent oral administration, and side effects. In fact, despite being optimized on therapeutics that are currently available, many people with Marfan syndrome still have to undergo one or more surgeries to repair their aorta. The use of antisense oligonucleotides (ASO) to inhibit angiotensinogen (AGT) is a novel approach to prevent aortic dilation in people with Marfan syndrome. This technology is differentiated from currently available therapeutics in multiple ways. In addition to the fact that it might be superior in efficacy, AGT-ASO is expected to be administered via monthly subcutaneous injection, which decreases the risk of sudden withdrawal from daily therapy. Although initial work will focus on the treatment of people with Marfan syndrome, AGT-ASO also has a high potential to benefit people with related conditions, such as Loeys- Dietz syndrome types 1-6, vascular Ehlers-Danlos syndrome, Familial Thoracic Aortic Aneurysm and Dissections, and acquired aortopathies. KYNETIC funding will support experiments to evaluate global vs liver-specific AGT-ASO, compare efficacy against standard of care therapy, evaluate toxicity, and define the ideal age of therapy administration. These crucial studies are necessary for designing future clinical trials and preparing an FDA application. Drs. Sheppard, Daugherty, and Lu have filed a provisional patent application for the use of AGT-ASO therapy in people with Marfan syndrome. The team is led by Dr. Mary B. Sheppard, M.D., a board-certified Family Medicine physician, who founded the University of Kentucky Aorta Clinic and is a doctoral candidate in clinical and translational science. The team also includes Alan Daugherty, Ph.D., Senior Associate Dean for Research and Chair of Physiology in the University of Kentucky College of Medicine, as well as Dr. Hong Lu, M.D., Ph.D., a Cardiology-trained physician scientist. Each investigator brings unique strengths to the team: Dr. Sheppard is an NIH- funded investigator in the field of Marfan syndrome, Dr. Daugherty is an NIH-funded investigator in the field of mouse models of aortic disease, and Dr. Lu is an NIH-funded investigator in the study of the renin-angiotensin system.