VCU news

By Jeff Kelley

Scientists at Virginia Commonwealth University’s School of Medicine are leading research to find a cure for fibrosis, building off a recent Nobel Prize-winning discovery that has revealed a gateway into the scarring diseases.

Found in the lungs, heart, liver and other organs, fibrosis is marked by overgrowth, hardening and scarring of tissue -- a result of inflammatory reactions that can be spurred by infections, allergic responses, tissue injury, radiation and other factors. Idiopathic pulmonary fibrosis, or scarring of the lung, is a well-known form of the condition, often the result of inhaling dust or fibers.

In IPF, fibrotic tissue disrupts and replaces normal alveoli, where gas exchange occurs, and increasingly makes it difficult to breathe. The disease can impact patients’ quality of life, with respiratory failure and even death, in severe cases, among the risks.

At VCU, Patricia Sime, M.D., chair of the Department of Internal Medicine, has formed a multidisciplinary team studying the unusual presence of a protein they have found in fibrotic lung tissue. The protein, Piezo2, is a “force-sensitive ion channel” – it acts as tiny gates on the outer walls of cells, helping them respond to stimuli such as pressure, stretch and touch.

Sime and her team, which includes her immunologist colleague and assistant professor Thomas Thatcher, Ph.D., and postdoctoral fellow Maggie Freeberg, Ph.D., propose that when the lungs stiffen because of fibrosis, Piezo2 detects this change and triggers a series of cellular reactions that may worsen the condition by promoting more fibrosis.

With that theory in place, they are investigating drugs that could treat and even cure IPF, and other fibrotic organ-scarring diseases, by blocking Piezo2.

“We’ve been able to show that there’s an increased amount of Piezo2 in scarred lung tissue from patients,” Sime said. “Now we have to show that it drives fibrosis so we can target it therapeutically and prevent the progression of scarring. Our overall goal is to develop new therapies to cure fibrosis and save the lives of our patients.”

Nobel discoveries and personal connections

Scripps Research molecular biologist Ardem Patapoutian, Ph.D., was awarded a joint 2021 Nobel Prize for his discovery of the Piezo1 and Piezo2 (“pie-yay-zoh”) channels, which are responsible for sensing and responding to environmental changes. Piezo2, which helps cells detect changes in stiffness or pressure, is normally found in nerves. But VCU researchers have discovered that Piezo2 is also involved in abnormal behavior of fibroblasts, the lung cells that play a role in the scarring process.

There are two FDA-approved antifibrotic treatments for some lung-scarring diseases. The drugs slow progression in some patients, but there is no cure except for lung transplantation. The market for IPF treatment is expected to grow nearly 40% to $6.01 billion by 2028, according to Mordor Intelligence.

Sime noted that her team’s potential treatment, currently focused on the lungs, could be tested to treat fibrosis in other organs, too.

Sime’s journey down the Piezo2 pathway began at the University of Rochester. There, she was working with a support group of patients living with pulmonary fibrosis and got connected to Rochester biomedical engineer Freeberg by the leader of the group: Freeberg’s mom, Mary.

Freeberg’s father and Mary’s husband of 40 years died of IPF in 2015. When she met Sime, Freeberg was researching tendon repair in orthopedic surgery; Sime convinced her to bring her professional talents and personal connection to the fibrosis field. After Sime was recruited to VCU in 2019, she also recruited Freeberg to come to Richmond.

In researching the body’s sensors (called mechanoreceptors) that detect pressure and movement in the lungs, Freeberg noticed that Piezo2 receptors kept appearing in her assays.

“We’ve since been analyzing the Piezo2 pathway and trying to screen it in human tissues, lung function and doing preclinical studies to determine how important it is in the development and progression of pulmonary fibrosis,” Freeberg said. “We’re really chipping away at this.”

The power of VCU partnerships

They believe Piezo2 is so important to the lung-scarring process that they have turned to finding ways to stop the receptor from reacting. Their resource-intensive, expensive work isn’t easy.

New drugs face significant regulatory hurdles and a long road of pre-clinical studies, which the team doesn’t expect to complete until at least 2026 (it often takes years to perform clinical studies). The field of fibrosis research is also highly competitive, and many other researchers and pharmaceutical companies are exploring potential therapies.

The first step to their drug development is creating a highly detailed and complex 3D computer model of the Piezo2 structure to understand how it works. Within the virtual model, they can screen millions of chemical compounds and narrow down potential drug formulations that can prevent the lung-scarring pathological response of Piezo2.

To build those models, Sime’s team is collaborating with the VCU School of Pharmacy, which has contributed expertise in computer-aided drug discovery and computational structural biology. The Piezo2 model was created with the help of professor emeritus Glen Kellogg, Ph.D., and research scientist Balaji Nagarajan, Ph.D., both in the Department of Medicinal Chemistry.

In their efforts, the team has utilized the only known Piezo2 inhibitor: a natural compound derived from spider venom, but it’s difficult to synthesize for use as a drug and comes at a high cost.

“Finding a treatment for fibrosis is like finding a needle in a haystack, but a computer model makes it a much smaller haystack. Visualizing the Piezo2 receptor and potential inhibitor compounds is necessary for us to see how the two might bind, which helps the medicinal chemists understand how the inhibitor might work,” Freeberg said. “We are also trying to identify something that will prevent the opening of Piezo2, because that opening is what causes the downstream pathologic response in response to organ scarring and stiffness.”

Once the computer model narrows the focus on the most promising inhibitors, the second stage is performing actual high-throughput lab tests using the actual compounds. “At the end of this, we hope to have five compounds to explore for future drug development,” Freeberg said.

Funding and what’s next

Sime’s team is funded by a $50,000 Commercialization Fund award from the Office of the Vice President of Research and Innovation. Such funds, she said, are extremely helpful in early experiments and providing the preliminary data that can help the team successfully compete for larger research grants, including those from the National Institutes of Health. Their work is also supported by Freeberg’s Pulmonary Fibrosis Scholars grant and a Parker B. Francis Fellowship.

After disclosing their technology to VCU TechTransfer and Ventures, licensing manager Magdalena Morgan, Ph.D., connected Sime’s team with Kellogg and Nagarajan in the School of Pharmacy.

“Dr. Sime and her team are all experts in their field, and their work with Piezo2 is illustrative of how a group of multidisciplinary researchers can bring their talents together to solve a problem and ultimately improve or save lives,” Morgan said. “And by conducting their research at an academic medical center and research institution like VCU, they gain access to all the necessary resources they need to move their fibrosis therapy development forward.”

Sime said the School of Pharmacy’s involvement has rapidly advanced their work.

“Working together, we are accelerating the pace of discovery to bring new therapies to patients in need,” she said. “The mission-driven nature of VCU research is what drew me here, and there’s been a lot of willingness to collaborate and succeed.”