A one-time treatment using small molecules to target progenitor cells, pioneered in the lab of a Harvard Stem Cell Institute researcher, may potentially restore hearing lost from some of the most common causes

By Alice McCarthy

Often regarded as a quasi-inevitable consequence of getting older, hearing loss affects a wide range of people. In fact, approximately 15% of American adults (37.5 million) aged 18 and over report some trouble hearing. Not only does hearing loss frustrate normal daily activities; it can impact social interactions, and is linked with depression, impaired cognitive function, and an increased risk for dementia. Fortunately, research initially conducted at the Harvard Stem Cell Institute is now the basis for a new approach to potentially restore hearing for individuals with sensorineural hearing loss, a condition that can be caused by age, noise, viruses, or other events.

For Jeff Karp, PhD, principal faculty member of the Harvard Stem Cell Institute, finding a solution to hearing loss and other medical conditions through stem-cell based regenerative medicine has been one of his lab’s goals for several years. In one of his major efforts, Karp is pioneering a small-molecule program designed to stimulate progenitor cells in the inner ear to grow the hair cells responsible for hearing. Karp collaborates closely with MIT’s Robert Langer, ScD, on this research.

“We wanted to radically simplify the main mode of stem cell therapy, which has involved taking cells out of the body, manipulating them, and putting them back into the body,” Karp says. His idea was to directly target stem cells and progenitor cells — cells that eventually become other types of cells — by delivering combinations of small molecules directly into the area affected. “If we could get these combinations of molecules into the body at very targeted sites, we might be able to then manipulate and control the stem cells and progenitor cells to some degree and turn on regenerative processes.”

Starting in the Gut

The concept grew from Karp’s research into the lining of the intestine, which regenerates every five to seven days. His team observed that stem cells of the intestinal lining carry a receptor called LGR5 on their surfaces. After studying the microenvironment and important signals that encourage gut stem cells to divide, they homed in on specific pathways with small molecules to control the division of stem cells as well as maintain them. With that information understood, the team looked for other biological systems with an abundance of LGR5 on their cell surfaces.

“One clear example was the progenitor cells in the inner ear,” recalls Karp. “We were excited about this because 90% of hearing loss has to do with the death of the hair cells.” He immediately set to work to see if the molecules discovered in their studies of the intestine could promote the proliferation of inner ear progenitor cells, grow new hair cells, and essentially regenerate hearing.

While stem cells in the gut constantly divide, progenitors in the mammalian inner ear do not divide after birth. “For some reason, in mammals like humans the brakes had just been put on,” said Karp. In 2015, his team tested the molecules from the intestinal studies to see if they could proliferate and maintain the “stemness” on the inner ear LGR5 progenitor cells. “I’ll never forget this,” Karp recalls. “When I saw the images I said, ‘I think we have a breakthrough here’ because of the beautiful images of these progenitor cells which had divided and formed new hair cells.”

Every experiment that the team conducted demonstrated that these cells appeared to have many distinguishing features of sensory hair cells.

Moving into Clinical Studies

Realizing their technology needed to get into patients quickly, Karp teamed up with Chris Loose, a former colleague from the Langer lab, and David Lucchino to co-found a commercial company called Frequency Therapeutics to take the approach to clinic.

The company’s lead drug candidate, FX-322, has now completed five clinical studies in a total of about 200 patients. “It’s actually a combination of two drugs,” said Loose, Frequency’s chief scientific officer. “Part of Jeff’s key breakthrough is you need to push on some of the key genes to activate these progenitors, but you also need something that can simultaneously act as an epigenetic agent to open targets. This combination of opening targets and pushing on the right targets simultaneously enhanced the effect.”

Trial results to date reveal that improvements in hearing were seen predominantly in two types of hearing loss, including noise-induced or sudden onset sensorineural hearing loss.

“The trials show really striking improvements in speech perception — the ability to understand speech and recognize words — which is the number one thing that matters to a patient,” said Loose. “That's what matters at home, school, and professionally.”

Improvements can be seen as quickly as 90 days after treatment with some individuals maintaining results for two years or more. Frequency recently completed enrollment of a Phase 2b study of 142 patients at more than two dozen sites in the US, with data anticipated in Q1 of 2023.

“Part of the exciting aspects of regenerative science is that it is disease-modifying,” said Loose. When a progenitor cell is activated, and makes a new hair cell, people can carry that cell for decades, potentially throughout their lifetime. “And there are no genetic changes; the drugs just turn on the natural genes that were already active in the native cells.”

Frequency is now using a similar approach to develop a treatment for remyelination in multiple sclerosis (MS), where the immune system attacks the myelin in the brain and central nervous system which is essential for nerve function and survival.

Meanwhile, Karp continues to work on other regenerative medicine projects in his lab. Just within the last year he has initiated a program involving small molecules for eye diseases and vision. “It’s highly exploratory right now but we are taking that process that we used in the intestine studying signaling pathways and seeing if we can find molecules that replicate and control the biology of stem cells and progenitor cells in the eye,” he said.

Karp is also the Distinguished Chair in Clinical Anesthesiology, Perioperative and Pain Medicine at Brigham and Women’s Hospital, Professor of Anesthesia at Harvard Medical School in Boston, and an affiliate faculty member at the Broad Institute and at the Harvard-MIT Division of Health Sciences and Technology.