Matt Springer

Joint project with Anders Näär

The Springer lab has decades of experience applying cell/gene/drug therapeutic approaches to cardiovascular diseases, and the Näär lab has uncovered several miRNAs as crucial regulators of cholesterol/lipid homeostasis and whole animal metabolism, with important ramifications for the treatment of cardiometabolic diseases. Together, they propose to develop a commercially viable therapy for three forms of cardiac disease: heart failure, smoking-related cardiac dysfunction, and Barth Syndrome cardiomyopathy. 

A Heartfelt Mission: A Bakar Fellow’s Approach to Heart Failure Therapeutics

By Niki Borghei

October 24, 2023

Tackling the multifaceted problem of heart failure is no easy feat. Heart failure can arise from various factors, including the wear and tear of time, the aftermath of a heart attack, unhealthy habits like smoking, and even genetic conditions. These factors all converge in how the heart responds to these challenges. Dr. Matt Springer, Professor in the Division of Cardiology at the UCSF Department of Medicine, aims to get to the “heart” of the problem by developing a therapy for three forms of cardiac disease: heart failure, smoking-related cardiac dysfunction, and Barth Syndrome cardiomyopathy.

Early experiments with therapeutic delivery have yielded promising results, pointing to the potential of an antisense oligonucleotide (ASO) developed by his Spark Award collaborator, Dr. Anders Näär. This ASO aims to interfere with a microRNA that plays a role in the progression from various factors to heart failure.

Q: What’s the science behind your solution to heart failure?
A: Genes, the stretches of DNA in your cells that hold most of the blueprint for how everything in the cell works, are always present, but they send out specific instructions in the form of RNA molecules only when a particular process should occur. This is usually a good thing, but when the heart or another tissue is injured, many genes respond by sending out RNA instructions and some of those can actually cause their own problems—it’s not a perfect system. An “antisense oligonucleotide” (ASO) is essentially a mirror sequence to a specific RNA molecule that interferes with it carrying out its purpose. My research group and Dr. Näär’s research group are collaborating to use an ASO that interferes with a particular RNA that is presumably beneficial in some circumstances, but seems to be playing a role in making things worse when the heart is stressed. Our planned research will enable us to determine how to use this ASO as a therapeutic treatment for heart failure resulting from these varied causes in humans.

Q: How did you develop an interest in cardiovascular disease?
A: I’ve been interested in cardiovascular disease for several decades. I first got involved in the field in the early 1990s at Stanford—I know, I know, but I’m a Cal alum so it’s ok—when I was trying to use gene therapy to modify skeletal muscle to secrete therapeutic proteins into the blood. We could only deliver small amounts into the bloodstream, so I decided to try also genetically engineering that part of the muscle to produce proteins that stimulate blood vessel growth (angiogenesis), hoping that the increased blood vessels could carry away more of the protein of interest. That’s the part that ultimately led to my career and got me interested first in angiogenesis gene therapy in muscle and heart, and then later at UCSF, cell therapy in the heart. Because UCSF has had a very strong history of smoking research, I have become fascinated by not only possible therapies for heart attacks and other cardiac diseases, but also using models to study cardiovascular effects of smoking tobacco and marijuana, vaping, being exposed to secondhand smoke, etc.

Q: What made you want to take the leap into entrepreneurship?
A: Despite being a Professor of Medicine, I come from a very basic science background (PhD in grad school, rather than MD in med school). I cut my teeth in basic research, but during my postdoc years, I started having a bit of an identity crisis in that while I felt strongly that basic research was important, I wanted my own work to have a more direct impact on health that was easier for me to visualize. We called it applied research in those days and it was a dirty word in some academic circles, but fortunately for me, what was ultimately rechristened as “translational research” came into its own, right around the time I was experiencing this fork in the road. What I like the most about the various research projects in which I’m involved is when they can improve public health, either by potentially leading to a treatment for genetic and acquired cardiovascular diseases, or by uncovering information that can change people’s personal health decisions. The opportunity to use my background and research experience to participate in development of promising therapeutics that ultimately help people clinically, especially those with high efficacy and surprisingly straightforward delivery, is very exciting.

Q: Tell us about your experience working on a joint project with your team.
A: Well, Anders (Dr. Näär) is great, and so is his student Melissa. I’ve been so impressed by their ideas and implementation. Dr. Xiaoyin Wang, who is the lead scientist working with me, and Anders and Melissa have made for a very innovative and productive team. We all bring different expertise and ideas to the table. It’s also a special thrill for me to have this new connection to UC Berkeley, which is what originally brought me to the Bay Area in the 1980s
for college.

Q: When do you expect to see the initial application of your project?
A: That’s always a tough question to answer. Fortunately, therapeutic delivery of this ASO is remarkably simple and seems to avoid many of the complexities of most molecular therapies or cell therapies; it’s essentially a drug despite being a nucleic acid (like DNA and RNA). The response in our models (with the caveats that these entail) has been startlingly effective, so when it comes to showing efficacy data, I don’t envision much problem there. But the regulatory steps are a black box to me; I hope to learn more about the process thanks to the Bakar Fellowship.