Damaged hair cells

This article I wrote for Hearing Tracker is about potential treatments for hearing loss.  Are you hopeful?

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 devices.  But 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 of the research efforts are focused on the cochlea since malfunctioning cochleae are the cause of almost all sensorineural hearing loss.  Understanding how the cochlea works and learning how to fix it is the central challenge.

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 (stereocilia) that ripple and sway as they respond to vibrations that are passed on by the ear drum.

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 the stereocilia into electrical signals that are sent to the brain for processing.

They are fragile microscopic marvels, explains Dr. Matthew Kelley, Chief of the Laboratory of Cochlear Development at the National Institutes of Health (NIH).  “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, and as we age  they get damaged or simply die off—and our hearing fades.  Once they are gone, they are gone, never to be replaced. Or are they?

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.”

In other words, we are only halfway on the road to even identifying all of the genes involved and what their roles are.

Gene Therapy or a Drug?

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”, says Professor Peter Barr-Gillespie, the scientific director of the Hearing Restoration Project, an international consortium of researchers.  “One, some sort of gene delivery where we would identify the gene that can overcome the blocks to regeneration.”

“But what I would prefer to see is some sort of drug that 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.”

Prof. Stefan Heller of 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 hybrids, a combination of the biological and the mechanical: a genetic or drug treatment paired with hearing aids.

Even partial restoration of “natural” hearing would give hearing care providers more to work with when fitting hearing aids. For example, the ability to partially improve a severe to profound hearing loss—or almost complete deafness—to a moderate hearing loss would be life-changing to millions of people globally. Audiologists could also play an important role in diagnosing specific causes of cochlear malfunction as they become better understood.

Any predictions should also take into account the possibility of a lucky break, a chance discovery that leads to a breakthrough. 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.”

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 four of the more prominent contenders:

Otonomy

Otonomy 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 a larger study released in October 2022 were less than promising.

But Otonomy is also working on another potential treatment called 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,” says Alan Foster, Otonomy’s Chief Scientific Officer, “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 because they lack Otoferlin, a protein that enables communication between the hair cells and the brain.  DB-OTO is designed to kick start Otoferlin production.

The second therapy now undergoing trials is designed to mitigate the effects of chemotherapy on a cancer patient’s hearing.  One of the more common chemotherapeutics 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 launched the first, and so far, only hearing loss related drug to be approved by the FDA.  It’s called Pedmark and has been shown to reduce the risk of hearing loss in children undergoing Cisplatin chemotherapy.  It’s a sodium thiosulphate compound similar to the one being developed by Decibel for the same purpose.

Fennec launched Pedmark on the U.S. market in October 2022.  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

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.

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(An expanded version of this article can be found HearingTracker.com)