The Quest for a Hearing Loss Cure: A Progress Report on Drug and Gene Therapy Treatments

To be clear, there is no cure for hearing loss and there is no treatment available other than hearing aids, cochlear implants, and other amplification and implant devicesBut there is hope.

You can find it in university labs, research centers, and private companies around the world. They are producing some very encouraging results, and the day is coming when some form of therapy will move from the lab to the ear.

Virtually all research efforts are focused on the cochlea, since malfunctioning cochleae are the cause of almost all sensorineural hearing loss. The work concentrates on what many refer to as the “3 R’s of hair cell research”: Repair, Rescue, and Regeneration. The central challenge is in understanding how the cochlea works, and how we might fix it or prevent it from becoming irreparably damaged in the first place.

Cochlear hair cells and auditory neurons: the center of hearing

The cochlea is about the size of a pea and is shaped like a spiral shell. Aptly, cochlea is the Latin name for snail. Inside there’s a fluid-filled tunnel lined with an array of tiny hair cells (called stereocilia) that ripple and sway as they respond to vibrations that are passed on by the ear drum.

Damaged Hair Cells

Inner-ear hair cells are responsible for converting mechanical vibrations into electrical signals that are then relayed to the brain. Up to 30% to 50% of hair cells can be damaged or destroyed before changes in your hearing can be measured by a hearing test. But when they're gone, they're gone—at least until some researchers find a new treatment.

Picture seagrass underwater, waving back and forth in the current. In effect, hair cells turn sound into movement. At the base of the hair cells are auditory neurons, the roots if you will. This specialized cluster of cells turns the movement of stereocilia into electrical signals that are sent to the brain for processing.

They are fragile microscopic marvels, Dr. Matthew Kelley, Chief of the Laboratory of Cochlear Development at the National Institutes of Health (NIH) told HearingTracker. “If you were to lay eight hair cells side by side they would be barely as wide as one hair on your head.”

We are born with some 16,000 hair cells in each of our two cochleae. That’s all we get. As we age, these hair cells get damaged or simply die off—and our hearing fades. Once they are gone, they are gone, never to be replaced. Or are they?

Regenerating hair cells, and some good news for deaf chickens

In 1988, researchers at the University of Washington discovered a tantalizing clue. They found that deafened birds can regenerate their lost hair cells. Could the human cochlea be coaxed into performing the same trick?

We are beginning to see hints that the answer is a qualified yes.

All mammals, including humans, lack the bird’s ability to regrow their hair cells. But in 2015 a team at Boston Children’s Hospital and Harvard Medical School reported that they were able to use gene therapy to restore some measure of hearing to deaf mice.

We are still a long way from being able to perform the same trick on humans. For example, as Dr. Kelley points out, “There are about 200 genetic loci that are thought to be related to hearing loss. Those are the specific locations in the genome that are associated with hearing loss. But so far in only about 100 of those locations have the specific genes been identified.”

Matt Kelley And Colleagues 1200x675

Matthew Kelley, PhD, (middle of back row) and his colleagues in the Laboratory of Cochlear Development at the National Institutes of Health (NIH) have been researching cellular and the molecular development of the mammalian cochlea.

In other words, we are only halfway along the long road to identifying all the genes involved and what their roles are–let alone to how we might manipulate those responsible for hearing loss.

Gene therapy or a drug for hearing loss?

Once a malfunctioning mutated gene is identified, the question becomes how can it be fixed? There are two ways to answer that question.

“There are a couple of possibilities,” explained Peter G. Barr-Gillespie, PhD, the former scientific director of the Hearing Restoration Project, an international consortium of researchers, and professor at the Oregon Health & Science University in Portland to HearingTracker. “First, some sort of gene delivery where we would identify the gene that can overcome the blocks to regeneration.”

Peter Barr Gillespie 1200x675

Peter G. Barr-Gillespie, PhD, works with a group of researchers taking part in the Hearing Health Foundation’s Hearing Restoration Project, reportedly the first international research consortium investigating the regeneration of sensory cells as a cure for hearing loss and tinnitus.

“Second, and what I would prefer to see, is some sort of drug you could either take by mouth or apply through the ear. The first step we are interested in is finding the right targets and then developing the drug.”  

Stefan Heller, PhD, who is in charge of the Heller Lab at Stanford University, says there will likely be no one eureka moment or across-the-board breakthrough. “It will be a long process, much like the fight against cancer. There is no single cure for cancer but there are now very successful treatments for various forms of it.” Heller expects the treatment of hearing loss will follow much the same pattern.

The first treatments to appear will likely be a hybrid combination of the biological and the mechanical: a genetic or drug treatment paired with hearing aids or cochlear implants.

Hearing Restoration Project Director Lisa Goodrich, PhD, and Ronna Hertzano, MD, PhD, present the 2021 webinar "The Present and Future of Inner Ear Hair Cell Regeneration.” Closed captions are available on this video. If you are using a mobile phone, please enable captions clicking on the gear icon.

Small breakthroughs could bring large consequences

A “cure” for hearing loss doesn’t necessarily have to take the form of a homerun. Even partial restoration of “natural” hearing would give hearing care providers more to work with when fitting hearing aids. For example, the ability to improve a severe-to-profound hearing loss to a moderate hearing loss would be life-changing for millions of people globally. It could also mean the difference between someone being able to opt for a hearing aid instead of cochlear implant surgery.

Additionally, one of the many challenges audiologists face when fitting hearing aids is people who perceive distortion and/or have less tolerance when hearing louder sounds (called “loudness recruitment” or “reduced dynamic range”). If we could find a way to repair or regenerate parts of the cochlea and restore normal loudness perception and fine-tuning, then the problem would just become a matter of fixing hearing sensitivity through amplification–a much easier job.

Genetic Research Clipping 1200x675

A successful gene therapy and drug treatment could mean the difference between someone being able to use a hearing aid versus needing a cochlear implant.

Finally, audiologists could also play an important role in diagnosing specific causes of cochlear malfunction as these problems become better understood. Diagnostic proficiency should increase as our understanding grows about cochlear dysfunction and repair.

How long before we find some cures for hearing loss?

Although there are some bright areas for specific types of hearing loss, we’re not going to sugar-coat it: you shouldn't postpone getting a hearing aid or cochlear implant out of hope for a revolutionary cure.

But any predictions should consider the possibility of a lucky break or a chance discovery that leads to a new treatment pathway. After all, science and serendipity often go hand in hand. Back in 1928 a stray fleck of mold came in through an open window in Alexander Fleming's laboratory, landed in his petri dish, and killed the bacteria in it. The result was penicillin.

The big question is, of course, when will any therapy be available? Barr-Gillespie, like many researchers in the field, talks in terms of 5 to 10 years. But he adds, “We could be surprised.”

Five promising hearing loss treatments in the research pipeline

In all, there are some 35 companies now working to bring a therapy to market, although the bulk of them deal with a specific type or cause of hearing loss.

Here’s a look at five prominent examples, several of which demonstrate how companies are racing against each other in a high-stakes competition of drug and gene therapy development.

Frequency Therapeutics FX-322

Frequency Therapeutics is forging ahead with FX-322, its lead candidate drug for hearing restoration in its research pipeline, despite the fact that it did not perform as hoped in the latest clinical trial.

The company remains optimistic. “We believe in the potential of FX-322.” says CEO David L. Lucchino. “We now have two independent, single-dose studies showing a hearing signal with FX-322 and with statistically significant improvements in speech intelligibility.”

“We recently obtained valuable data from two clinical studies in patients with sensorineural hearing loss that have provided us with important learnings that already are informing our future development plans for FX-322,” says Lucchino.

Otonomy OTO-413 and OTO-6XX

Similar to Frequency, Otonomy also had disappointing results in the latest round of Phase 2 trials for its candidate treatment OTO-413 which is intended to repair the connections between inner hair cells and auditory nerve fibers in the cochlea that are damaged due to noise or exposure to ototoxic chemicals. Despite the promise of early small-scale trials, the results of the larger study released in October 2022 were less than promising.

Alan Foster

Alan Foster, PhD, of Otonomy.

But Otonomy is also working on several other potential treatments, including OTO6XX.  While other companies are trying to grow new hair cells, Otonomy is taking a different approach: repair rather than replace.

“If you can find a way to repair damaged hair cells,” Otonomy Chief Scientific Officer Alan Foster told HearingTracker, “then you will be able to restore hearing without having to regenerate a whole cell. So that’s the theoretical basis behind it, and we’re still at an early stage. But we’ve identified some mechanisms that we think are going to be beneficial.”

OTO6XX is now in pre-clinical development.

Decibel Therapeutics

Decibel is developing a suite of genetic and drug therapies to treat hearing loss and balance disorders. Two of them are now in clinical trials.

The first is dubbed DB-OTO and it promises to treat children who are born deaf due to a lack of Otoferlin, a protein that enables communication between the hair cells and the brain. DB-OTO is designed to kick-start Otoferlin production and has now been cleared by the FDA for human trials. Two other drug companies, Akouos (AK-OTOF) and Sensorian (OTOF-GT), are also in hot pursuit of gene therapies to treat otoferlin deficiency, with Akouos being purchased by drug giant Eli Lilly for $487 million in October 2022.

Decibel Therapeutics CEO Lawrence Reid, PhD, talks about the company's hearing restoration treatment research in this 2022 YouTube video.

Another therapy from Decibel, now undergoing trials, is designed to mitigate the effects of chemotherapy on a cancer patient’s hearing. One of the more common chemotherapeutics in cancer treatment is Cisplatin, and it can damage hair cells leading to permanent hearing loss. DB-020 is designed to deliver a formulation of sodium thiosulfate, a naturally occurring metabolite, into the cochlea where it inactivates Cisplatin to prevent damage. That is the hope, and so far, early results are encouraging.

Decibel also has another five potential therapies for the ear in its pipeline, including one as yet unnamed possible treatment specifically aimed at hearing loss. It is still in the research phase.

Fennec Pharmaceuticals

Fennec has been in a race with Decibel, and in October launched the first, and so far only, hearing loss related drug to be approved by the FDA. Called Pedmark, the new sodium thiosulphate compound is similar to Decibel’s DB-020 and has been shown to reduce the risk of hearing loss in children undergoing Cisplatin chemotherapy. 

HearingTracker Audiologist Matthew Allsop breaks the news about Fennec's approval from the FDA of Pedmark.

That’s great news for the 5,000 American children who receive cancer treatment with Cisplatin or similar drugs every year. Cisplatin is used to treat a range of cancers in children including liver, bone, and brain cancer. But it’s ototoxic and can cause permanent hearing loss.

Until now, the only remedies were hearing aids and cochlear implants.


Rinri’s strategy appears to be unique. Unlike the other contenders, their initial focus is not on repairing or restoring hair cells. Instead, they are working on restoring the auditory neurons that sit at the base of the hair cell and produce the electrical signals that are transmitted to the brain.

“We reckon 75% of all sensorineural hearing loss is caused by damage to the hair cells,” says Rinri’s CEO Dr. Simon Chandler. “But the remaining 25% is either caused by damage or loss of auditory neurons alone or in combination with the death or damage to both the hair cells and the auditory neurons.”

Rinri’s initial focus is on restoring the auditory neurons in part because regrowing hair cells is the more difficult challenge. Another reason is that regenerating those neurons might be good news for those receiving cochlear implants.

“Cochlear implants are great,” says Chandler. But they have their limitations. “So what we can do, in the initial stages, is look at acting as an adjunctive therapy for cochlear implants and actually improve the performance of cochlear implants. But ultimately we are looking to replace them.”

“We're about two years away from the first human clinical trials,” concludes Chandler.

The Quest Goes On

As shown, many companies are in hot pursuit of treatments for various forms of hearing loss, and some are making good progress. Although hearing aids, cochlear implants, and other devices will probably remain the go-to treatments for hearing loss well into the future, it is hoped that drug and gene therapy solutions emerge soon that provide new treatment options and/or increase the effectiveness of current devices.