New School of Medicine research led by Lian-Wang Guo, PhD, a professor of surgery; Craig Kent, MD, chief executive officer of UVA Health, executive vice president for health affairs, and professor of surgery; and Coleen McNamara, MD, a professor of medicine and director of the UVA Beirne B. Carter Center for Immunology Research, is focused on developing targeted approaches for treating abdominal aortic aneurysm (AAA). The research is backed by a new $2.8 million grant from the National Institutes of Health.
AAA is a balloon-like bulge of the aorta, the largest artery in the body, caused by inflammation and degeneration of the aortic wall. A silent killer, AAA typically grows without symptoms, but can suddenly rupture, leading to mortality rates of 70% to 90%. Currently, effective medical therapy for AAA is lacking, primarily due to gaps in understanding its mechanisms and limitations in targeted drug delivery methods.
Preliminary studies by the researchers suggest that BRD4, an epigenetic “reader” known for activating specific gene sets by recognizing histone modifications, holds promise as a therapeutic target. They propose that abnormally increased BRD4 proteins, anchoring at specific genomic loci marked by histone acetylation, assemble enhanceosomes that activate genes responsible for aortic inflammation and degeneration. Therefore, targeting BRD4 overactivity—identified as the Achilles’ heel—by disrupting enhanceosomes could effectively avert aberrant gene activation without compromising normal gene activity.
Their strategies involve using small molecules to evict overactive BRD4 from the epigenomic landscape, or reducing BRD4 protein through PROTAC technology, akin to demolishing a skyscraper in Manhattan. These BRD4-inactivating agents will be precisely delivered using AAA-targeting, biomimetic, injectable nanoparticles developed in collaboration with MPI Professor Shaoqin Gong at the University of Wisconsin-Madison. Success in this endeavor could mark a major breakthrough in developing the first medicinal therapy for AAA.
Clint Miller, PhD, an associate professor in the Department of Public Health Sciences, serves as a co-investigator on the project. Collaborators include Jianjie Ma, PhD, Xinyu Zhou, PhD, Gary Owens, PhD, and Mete Civelek, PhD, at the University of Virginia, along with Bowen Wang, PhD, at Northwestern University.
Read more about School of Medicine research aimed at preventing abdominal aortic aneurysms in the Medicine in Motion story on April 24, 2024.