Connective Issues Fall 2025

Our new Research Grant awardees are blazing new pathways to understand and to help individuals with Marfan syndrome. We are excited by the advanced technologies that both our new Everest Award Grantee, Dr. Michael Fischbein, and our new Career Development Awardee, Dr. Alexander Bashore, are using to identify specific genes and proteins that drive aneurysm progression and may someday predict why di ff erent individuals in the same family have di ff erent clinical problems. Our new Victor McKusick Fellow, Dr. Matthew Duda, will also focus on why Marfan syndrome patterns candi ff er between men and women. In parallel, our Innovator Awardee, Dr. Bharath Ambale-Venkatesh, will be leading a team to develop virtual models of aortas to use modern computing algorithms to predict aneurysm formation and progression. Together, these approaches will lead to strategies to identify those patients who are at the highest risk of aneurysm rupture and dissection and suggest new treatment strategies to help them live long and healthy lives.

 Matthew Duda, MD – Stanford University Fibroblast Klf4 expression attenuates sex-specific aortic root aneurysm formation in a murine model of Marfan syndrome $150,000 2-Year Victor McKusick Fellowship This project will help researchers better understand the molecular processes that allow aneurysms to form in people with Marfan syndrome, including why men and womenarea ff ecteddi ff erently. The study team will first investigate how deleting a specific gene in fibroblasts, which is a major cell type responsible for generating connective tissue, changes the structure and function

of the aortas of mice engineered to have Marfan syndrome. Next, they will study how treating the Marfan mice with hormones changes their aortas. These findings could lead to identifying targets for precision therapies that can treat Marfan syndrome without surgery.

 Michael Fischbein, MD, PhD Stanford University

Multiomic characterization of inherited aortopathies $220,000 1-Year Everest Award (with the potential for $880,000 over four years) To create new and more e ff ective treatments for Marfan syndrome and LDS, the underlying biological causes of these conditions in people must be understood. The current lack of insight in this space is a significant hurdle for research. To tackle this problem, the study team proposes using advanced sequencing technologies to

analyze both healthy and diseased tissue samples from individuals with Marfan syndrome and LDS who have undergone surgery. By studying these tissues, researchers hope to gain insight into the exact cellular changes that contribute to disease progression. The team will also collect blood samples from patients and use similar techniques to identify signals in the blood that relate to the progression of the disease.

 Bart Loeys, MD, PhD – University of Antwerp The high need for a rigorous multi-lab pre-clinical study protocol and platform to combat aortopathy in Marfan syndrome $220,000 1-Year Everest Award (with the potential for $880,000 over four years) Less than 5% of early-stage pre-clinical studies advance to human trials, largely due to inconsistent and non standardized methods, especially in animal trials. This challenge is present in Marfan syndrome research, where mouse studies often yield conflicting results across

labs. Through this project, Dr. Loeys and his team aim to create a standardized, rigorously defined study protocol for Marfan syndrome research. This includes uniform approaches for selecting mouse models, determining dosages, preparing drugs, and analyzing outcomes. The protocol will be tested across multiple labs, followed by evaluation of a small set of the most promising drugs targeting well understood biological pathways in Marfan syndrome. By applying standardized methods, researchers can better identify the most viable drug candidates for human trials. CONT INUED

Craig T. Basson, MD, PhD, Scientific Advisory Board Chair

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