This story is one in an occasional series about advancing discoveries with clinical and commercial potential through collaboration and commercialization.

Jeff Karp

In the beginning, Jeff Karp, PhD, was not even thinking about how to reverse hearing loss. Ten years ago, Karp, who is now the Distinguished Chair in Clinical Anesthesiology, Perioperative and Pain Medicine at the Brigham, and his lab were focused on the gut, where the intestinal lining is regenerated every few days.

“One concept that has been at the cornerstone of our work is harnessing the power of stem cell regeneration for therapy,” said Karp. “Initially, we thought if we can take cells out of the body, manipulate them and put them back in the body, we could produce regenerative outcomes.”

This cell therapy approach, which has been used with great results in other settings, such as CAR-T therapy for cancer treatment, proved extremely complex when working with cells from the intestinal lining.

“While there’s enormous opportunity, it’s incredibly complicated,” said Karp. “So I asked the team, is it possible for us to apply the concept of radical simplicity here?”

By taking a step back and applying this new view to their work, the lab gained fresh insights into the cells that drive regeneration—and found a path forward to clinical translation. With the formation of Frequency Therapeutics in 2014, Karp and colleagues have since translated these discoveries into potential clinical applications, with clinical trials currently underway to regenerate the cells needed for hearing—and potentially reverse hearing loss for people with acquired sensorineural hearing loss. But long before the company and clinical trials began, Karp and his co-investigators at the Brigham and the Massachusetts Institute of Technology (MIT) were laying a strong foundation, built through years of perseverance and basic research discoveries.

Applying Radical Simplicity to a Complex Problem

See Karp’s TEDx talk on radical simplicity here.

At the core of Karp’s work is a key philosophy shared by many of history’s greatest innovators, including Leonardo Da Vinci: Simplicity is the ultimate sophistication. “If we want to help patients, we have to simplify in every possible way,” said Karp. “So we asked, is there a way to perform stem-cell-based therapy without removing cells from the body?”

In 2010, Karp, in collaboration with Robert Langer, ScD, at MIT and postdoc Xiaolei Yin, PhD, began with cells from the intestinal lining, examining their microenvironment and the signals that progenitor cells and their neighbors, Paneth cells, use to communicate. The team examined whether they could replace the cells with small molecules that could replicate those signals. One key receptor found on stem cells emerged from their work: LGR-5.

“Our first important discovery was that we were able to find small molecules that could control and manipulate stem cells from the intestine,” said Karp. “But we wanted to take a step back and ask, how can this lead to something bigger that can help more patients?”

A few years later, the team began applying their findings to progenitor cells found in the inner ear. Unlike cells in the gut, progenitor cells in the ear do not regenerate later in life. But the team discovered in the literature that these cells also had LGR-5 receptors. This suggested the small molecules they had identified from studies in the gut could be applied to control the proliferation of the cells in the inner ear.

The team knew it was theoretically possible to regenerate hearing later in life because the phenomenon occurs in other species, such as birds and reptiles. But was it possible for small molecules to restore hearing in humans?

A Resounding Success

Karp remembers a key moment in the project’s success. He was in Montreal in 2012 visiting family when Yin sent him images of data from some of the experiments recently conducted in the lab.

“When I opened the image, I was blown away,” said Karp. “I turned to my family and said, ‘I think we have a breakthrough.’ These are the moments you live for as an academic—I knew we were onto something special.”

The small molecules they had identified that promoted proliferation of cells in the gut had indeed helped the progenitor cells in the inner ear proliferate too, and the images Karp beheld showed the growth of bona fide hair cells, capable of sending and transmitting signals.

Anatomy of the ear

Hearing loss affects approximately one in three people between the ages of 65 and 74 and nearly half of adults older than 75. It can result from exposure to loud noise over a person’s lifetime, aging, disease and heredity. Devices for people who have hearing loss, such as hearing aids, can amplify sound, but do not necessarily provide the clarity of sound so important to understanding speech. Other devices, such as cochlear implants, can provide benefit but are invasive and do not provide some of the features of hearing.

“Our ears are born with about 15,000 hair cells per inner ear,” said Karp. “These hair cells are killed over time, causing hearing loss, but the nerves remain. If we can regenerate hair cells, they could reconnect to the nerves.”

After the breakthrough moment, Karp and his colleagues knew they were onto something big in the field of hearing regeneration.

“We thought this could lead to new therapeutics—it could be a gateway to unlocking the field of hair cell biology and digging deep into the regenerative process of hearing,” said Karp. “Instead of creating a few hundred cells in the lab, we could create thousands and thousands of cells.” But the team would need to take steps to move beyond the lab-based discovery toward clinical translation.

Creating Solutions for Patients

Karp has always been interested in research that can help society.

“During my PhD and postdoctoral fellowship, I trained with entrepreneurial academics,” said Karp. “I’m always looking for translational opportunities.”

In 2014, Karp and Langer approached David Lucchino and Chris Loose, PhD, who had recently sold a medical device company the pair had started with MIT’s Langer, and were looking for the next opportunity. Their conversations led to the formation of Frequency Therapeutics.

Since 2015, the company has helped develop small-molecule therapeutics and led clinical trials building upon Karp and Langer’s discoveries. Today, all work, including trials, is being done by Frequency Therapeutics. In August 2021, Langer, Karp and co-authors from the company published results in the journal Otology & Neurotology on results from a phase 1b study in 23 participants who had mild to moderately severe hearing loss. For the first time, their findings showed a hearing signal suggesting that it may be possible to restore hearing loss in humans using small molecules. Importantly, participants reported improvements in speech perception—an especially important outcome for many people with hearing loss. The company is now enrolling more than 100 patients in a large and rigorously controlled phase 2b study. Results are expected in early 2023.

Karp thinks about people affected by hearing loss every day.

“Hearing loss can have a profound effect on a person’s life—their livelihood is dependent on their hearing,” said Karp. “When I get emails from people with hearing loss, it’s fuel to go faster, to do more.”

Karp is grateful to have a team and colleagues that share his passion for improving patients’ lives and to have found a path to move their research toward clinical impact.

“We’re here to make discoveries, but that’s not where the work ends,” he said. “It’s all about finding ways to bring those discoveries to patients.”

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