Transformative heart and gene research inspired by life-changing events

Prof. Benjamin L. Prosser from the Perelman School of Medicine at the University of Pennsylvania is a pioneer in cardiac mechanobiology research and is developing new genetic therapies for rare neurological conditions. His ties to both fields are deeply personal.¹

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When I began my Ph.D. some 20 years ago, my focus was on the cellular and molecular biology of the broader skeletal muscle system. But after my grandfather and uncle both passed away from sudden cardiac arrest within about a week of one another, I was driven to shift my focus to research about the heart.

I already had an interest in studying muscle – which of course the heart is too – so this felt like somewhere I could dovetail with doing something good for my family. Personal connection has been a pervasive theme throughout my career.

We started the lab at Penn Medicine in 2014. Our research focuses on understanding the cytoskeletal and nuclear mechanobiology of the heart, with a strong emphasis on studying the cardiac microtubule network.

Mechanobiology studies the processes that control the heart's ability to generate forces and tune its performance in response to stimuli. When people exercise, have a fight-or-flight reaction, or when someone is pregnant, then the forces on the heart change, and it has to adapt both acutely and chronically. The heart must respond in seconds and minutes to change the body’s cardiac performance.

When I established the lab, we had decided to focus on studying how cells generate the forces that allow the pumping of the heart and the flow of blood. We wanted to understand on a molecular level how the heart responds to these changing forces.

One important avenue of research is the study of particular diseases like laminopathy, which is a mutation in a component of the nuclear envelope. Lamins are actually what provide the structural support to the nucleus. But when patients have mutations in the lamina, the nucleus becomes weak and fragile. Then the forces it normally withstands can actually cause nuclear ruptures and DNA damage. This can ultimately lead to the death of that heart muscle cell and the impaired performance of the heart.

Remember that inside the heart muscle cell, the nucleus is experiencing high contracting forces over and over again for each of the two billion beats that cell will undergo during your lifetime. It has to be structurally reinforced to be able to withstand that sort of high-stress environment.

By precisely mapping how the forces within the heart are transmitted through the cell’s structural framework into its nucleus, we've pinpointed the particular forces that are causing damage. We've essentially identified vulnerabilities that the nucleus has to the mechanical forces that can cause the nuclear envelope to rupture. From this we are now utilizing therapeutic approaches to shield that sort of fragile nucleus from the cytoskeletal forces causing the damage.

Protecting the fragile nucleus can spare the heart muscle cell and thus the heart, which hopefully allows for preserved performance in patients with these genetic mutations that otherwise cause devastating heart failure.

If we can translate our research into treatments for patients with laminopathy – who currently have no treatment options for this fairly devastating heart disease – then I think we could really make a difference.

A lot changed when my daughter Lucy was born in 2018 and started having seizures after about four days. She was diagnosed with STXBP1 encephalopathy, a rare genetic neurodevelopmental disorder. This dramatically changed the trajectory of our life, the lab and everything else.

In the couple of weeks after my daughter was diagnosed – when trying to learn about her disease and its consequences on the brain – I probably took in and retained more information than I'd ever done in my entire life. The hardest part of facing a rare-disease diagnosis is that initial feeling of helplessness. As a parent, all you really want to feel is that you could do something to help your child.

I feel incredibly privileged to be able to do the kind of work that I now do on these disorders. It’s almost an obligation, because there is something meaningful that I can do to help my daughter and others. Of course, I could not do any of this work alone. I’m fortunate that I brought colleagues into the team who have real expertise in neuroscience, as well as in the genetic therapies we need to pursue in the clinical presentation of these disorders. In addition, our Center for Epilepsy and Neurodevelopmental Disorders (ENDD), which spans both Penn Medicine and the Children's Hospital of Philadelphia, helps us bridge the gap between researching a particular rare disease and getting a new therapy into humans.

STXBP1 and SYNGAP1 are genes crucial for synaptic transmission and neural development. Disorders related to these genes – or synaptopathies – fundamentally affect how neurons transmit and receive information.

There are two copies of STXBP1 and SYNGAP1 in each of our neurons. But kids with a variant or mutation have only one copy. This means they have only about half as much STXBP1 or SYNGAP1 protein as needed to do the job in the neuron. It’s known as monogenic haploinsufficiency.

The proteins that these genes encode live at the synapse. That’s where one neuron interfaces with another neuron to communicate information. There's a presynaptic side sending the signal and a postsynaptic side receiving it. STXBP1 lives at the presynaptic side and SYNGAP1 at the postsynaptic side.

When you have mutations in one of these genes, then the ability of the neurons to properly communicate is disrupted. As neuronal communication is critical for everything we do – be it thinking, learning, speaking, or enabling memory and motor function – a breakdown has pervasive consequences on all aspects of affected kids’ lives. This can lead to severe neurological disorders, including epilepsy and intellectual disabilities.

Even though diagnosis of these disorders is relatively new, we understand the exact genetic underpinning. This is a big advantage in research. From a therapeutic development standpoint, our goal is very straightforward: we need to bring the protein back to normal levels.

To do so, we use both gene-targeted therapies and an RNA therapeutic intervention known as antisense oligonucleotides (ASOs). With these upregulation therapies, we’re really focusing on the root causes of these disorders. It’s a challenging interface, as we're trying to develop next-generation therapies to help this current generation of children.

As scientists, we accept the fact that the majority of experiments fail. You have to be able to ride those highs and lows; to push through the failures to reach eventual successes. When an experiment has direct implications for your daughter's health and well-being, it's harder to stomach the failures.

But with these new gene-targeted therapies coming online within the next year or so, it’s a particularly important time to be a parent scientist. We need to evaluate the tremendous potential of these therapies to help our kids, but we also need to really understand the associated risks. I value sharing the mindset of the family that will be bold enough to take the risk to try and benefit their child. It’s something I think about every day.

I'm most excited about the potential of viral-mediated delivery of genetic cargo to the brain to correct genetic neurological disorders. Many groups have made significant breakthroughs in this field in recent years. Researchers have developed viral delivery vectors capable of packaging large genetic payloads and delivering them to neurons across the brain regions affected by a particular disease. This approach holds tremendous promise for treating genetic neurological disorders.

In the next five years or so, we'll likely see these new therapies being tested in humans. We finally have something that could potentially treat disorders that have existed throughout human history. I’m struck by the significance of this moment – it’s truly remarkable.