Connective Issues Spring 2022

$200,000 AWARDED IN NEW RESEARCH GRANTS

In January, The Marfan Foundation announced $200,000 in new grants were awarded as part of its 2021 Research Grant Program. These grants include a fellowship award and a career development award. The newly-funded projects address aortic and optic issues in Marfan syndrome. “The recent grant awards from the Foundation re fl ect our commitment to supporting research that enables scientists to conduct critically important studies that require seed money for preliminary data in order to get larger government grants in the future,” said Dr. Josephine Grima, Chief Science O ffi cer for The Marfan Foundation. “With the addition of these grants, we are now funding a total of 33 research studies, which all have a common goal to improve the lives and bene fi t

those living with Marfan, VEDS, Loeys-Dietz, and other genetic aortic conditions.” The Victor McKusick Fellowship Award, $100,000 for a PhD over two years, is designed to support postdoctoral fellows embarking on a scienti fi c career in biomedical research related to Marfan syndrome or any of the genetic aortic or vascular conditions that are within the Foundation’s scope of interest. This award requires an institutional match where half of the funding comes from the Foundation and half from the sponsoring institution. The Career Development Award, $100,000 over two years, is designed to support investigators early in their career to derive preliminary data in a key concept area that has high potential to lead to extended funding from the National Institutes of Health (NIH), European Union (EU), and other large research funding sources.

RESEARCH GRANT RECIPIENTS VICTOR MCKUSICK FELLOWSHIP AWARD $100,000 ▸ Josephina Meester, PhD, Bart Loeys, MD, Mentor, University of Antwerp Pathomechanistic Study of Biglycan Mutations in Aortopathy Development The aorta is the body’s main artery and supplies oxygenated blood to all parts of the body. A dilatation (enlargement) of the aorta at the level of the thorax leads to the development of thoracic aortic aneurysms and dissections (TAAD). These weakened regions are vulnerable to tearing and this often results in sudden death. In 2017, the researcher identi fi ed BGN

(Biglycan) as a novel genetic cause of a severe form of TAAD, which is now called Meester-Loeys syndrome (MRLS). This novel syndrome shows features similar to Marfan syndrome and Loeys-Dietz syndrome. Based on the current knowledge, it remains unknown which molecular mechanisms explain how exactly these mutations in BGN lead to TAAD (MRLS). This project aims to further unravel the disease mechanisms underlying MRLS by using a technique called (single cell) RNA sequencing, allowing the researcher to determine which genes are (highly) active and which ones are not. This method will be applied on a male mouse model which lacks biglycan and that also leads to the development of aortic disease. The results will then be validated in a human cell model. The expected results will be bene fi cial for genetic counseling and clinical follow-up of the families. Furthermore, the study can lead to the development of more personalized preventive therapeutic strategies. In the long run, it is anticipated that the research group will also use these mouse and cell models for drug compound screenings for TAAD in general. CAREER DEVELOPMENT AWARD $100,000 ▸ Je ff erson Doyle, MBBChir, PhD, Johns Hopkins University Treatment of Axial Myopia in Marfan Syndrome using Prostaglandin Analogs

Severe near-sightedness is highly prevalent and can cause signi fi cant visual impairment in Marfan syndrome. However, the molecular mechanisms driving pathological eye growth in Marfan syndrome and therapies to combat it are almost entirely unexplored. This study will evaluate whether Prostaglandin analogues (PAs), a class of clinically-available eye pressure lowering eye drops used to treat glaucoma, a condition for which people with Marfan are at increased risk, can reduce severe near-sightedness in mice with Marfan syndrome. This

proposal aims to identify a novel way to reduce pathological eye growth in Marfan syndrome using a clinically approved class of drugs that could be easily translated into human use. The broader goal of this work is to better understand the mechanisms driving severe near-sightedness in Marfan syndrome to help identify new treatment strategies for this clinically-important but largely unexplored issue.

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