Use of Antisense Oligonucleotides Targeted Against Angiotensinogen in Marfan Syndrome
Project Abstract:
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 5000 people with no predisposition based on gender race or ethnicity Therapeutics for Marfanrelated 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 AGTASO 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 AGTASO also has a high potential to benefit people with related conditions such as Loeys Dietz syndrome types 16 vascular EhlersDanlos syndrome Familial Thoracic Aortic Aneurysm and Dissections and acquired aortopathies KYNETIC funding will support experiments to evaluate global vs liverspecific AGTASO 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 AGTASO therapy in people with Marfan syndrome The team is led by Dr Mary B Sheppard MD a boardcertified 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 PhD Senior Associate Dean for Research and Chair of Physiology in the University of Kentucky College of Medicine as well as Dr Hong Lu MD PhD a Cardiologytrained 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 NIHfunded investigator in the field of mouse models of aortic disease and Dr Lu is an NIHfunded investigator in the study of the reninangiotensin system
