At Washington University, training the next generation of leaders in translational medicine is a key focus. “The young people in our labs are smart and dedicated, and they know that what we’re doing will change medicine — 20 years, 10 years, 5 years from now,” Skip Virgin says. “It’s actually already happening, and they’re trying to figure out how to do it yesterday.”
Cheryl Leyns and Tien-Phat “Phat” Huynh are two of the promising graduate students spread out across the School of Medicine. Members of David Holtzman’s lab, they research pathologies of Alzheimer’s disease. Alzheimer’s is the most common cause of dementia and currently affects an estimated 5.5 million Americans. While the exact cause of the disease is unknown, it is characterized by the appearance of two types of protein aggregates in the brain. The amyloid-beta protein clumps together to form plaques outside of brain cells, while the tau protein forms tangles within the cells. Together, these are thought to drive the loss of brain cells, or neurodegeneration, that occurs in Alzheimer’s patient brains and cause the steady cognitive decline that clinically characterizes the disease.
Leyns is a doctoral candidate in the Molecular Cell Biology program in the Division of Biology and Biomedical Sciences. In the lab, she focuses on the tau protein, a driver of Alzheimer’s that also contributes to 25 other neurodegenerative diseases. And she’s worked on two key projects: 1. investigating novel therapies, and 2. examining novel mouse models, studying the risk factor TREM2 and how it’s impacting tau pathology and tau-mediated neurodegeneration.
Leyns spent her first three years designing gene therapy approaches to deliver biologics, namely monoclonal antibody constructs, to target tau protein. The benefits of gene therapy are that researchers can get past the blood-brain barrier and deliver the drug directly to its target. Leyns says the research was exciting but also frustrating at times, when the research team experienced technical issues and setbacks along the way. Today, the monoclonal antibody, licensed now to AbbVie, is in Phase II clinical trials.
“It’s been a great experience to be a part of investigating this biological therapy, its mechanism of action, and trying to optimize delivery of the drug, knowing that it may make an impact in patient care,” Leyns says.
In her most recent work, Leyns has been investigating the interactions between TREM2, tau and neurodegeneration. Certain variants of the TREM2 protein are risk factors for Alzheimer’s in people, and previous studies have shown that because these variants do not function properly, they exacerbate damage in the brain already instigated by amyloid plaques early in the disease. Surprisingly, Leyns found the opposite when examining TREM2 function in a tau mouse model, in that the loss of TREM2 function reduced inflammation in the brain and protected against neurodegeneration in the mice. These unexpected results indicate further research is critical in order to understand how TREM2 variants impact Alzheimer’s disease initiation and progression, and how to best target it therapeutically. The study, of which she is a lead author, is currently under review for publication.
“One of the benefits of being in Dr. Holtzman’s lab,” Leyns says, “is being part of translational science at such an early stage of my career — participating in meetings with pharma companies and biotech, understanding what they’re looking for in their drug development, and then being able to design basic science questions that address some of those needs and concerns in the field.”