The road to understanding the various causes of hearing loss and finding the most appropriate treatments has been figuratively as narrow and winding as the inner ear itself. But new imaging techniques using nanotechnology, as well as research advances in pharmaceutical treatments, may mean a wide range of solutions are within sight.
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December 2021“Right now, patients come in because they know they have trouble hearing,” said John Oghalai, MD, chair of the University of Southern California Caruso Department of Otolaryngology–Head and Neck Surgery and an otolaryngologist with Keck Medicine of USC in Los Angeles. “We give them a hearing test that documents their level of hearing loss, but we aren’t really treating anything or telling them more than what they already knew.”
One in five people worldwide live with hearing loss, according to the World Health Organization. Hearing disorders can cause people to be socially disconnected from others, impacting their ability to work and generally to communicate and socialize. This has been shown to lead to increased levels of dementia and depression. Conditions like severe tinnitus can impair sleep and quality of life and can also lead to depression.
“As physicians, we have nothing to treat these patients with today except behavioral interventions or distraction techniques,” said Jeffrey Harris, MD, PhD, distinguished professor of otolaryngology and neurological surgery at the University of California San Diego, and cofounder of biopharmaceutical company Otonomy, adding that most drug therapies use medications aimed at treating depression, while hearing aids assist with hearing difficulty and incorporate various masking strategies that are only marginally successful. “As a consequence, both physicians and patients are interested and hopeful that therapies will emerge that will allow us to address these highly prevalent hearing disorders,” he said.
New Tools for Inner Ear Imaging
Currently, the main diagnostic tools used to image the ear in a clinical setting are computed tomography (CT) and magnetic resonance imaging (MRI). According to Elliott D. Kozin, MD, an otologist and neurotologist at the Massachusetts Eye and Ear Infirmary at Harvard Medical School in Boston, although both CT and MRI are excellent tools, they have limits in terms of imaging resolution and consequently cannot capture microscopic structures for patients with hearing loss due to changes that occur at the cellular level (as opposed to larger anatomic changes).
“There are emerging imaging technologies, such as optical coherence tomography (OCT), that afford increased capacity to visualize the inner ear,” said Dr. Kozin. “The goal of these new imaging modalities is to better delineate inner ear microanatomy to understand the underlying causes of hearing loss.”
Dr. Oghalai’s research has given him confidence that the ability to diagnose the cause of hearing loss and target a treatment to that patient’s problem is on the horizon. This research, using OCT on transgenic mice, has found links between noise exposure levels, like those from a bomb blast, and inner ear nerve damage.
His most recent study, published in Frontiers in Cell and Developmental Biology, links this type of inner ear nerve damage to endolymphatic hydrops (Front Cell Dev Biol. Published online November 5, 2021. doi:10.3389/fcell.2021.747870). This latest study showed that while inner ear fluid levels in the cochlea of mice remained the same when exposed to sound levels of up to 95 decibels, the fluid rose at noise exposure levels beyond 100 decibels, equivalent to the sounds generated by a chain saw or motorcycle. A week after this noise exposure, the animals lost auditory nerve cells. The study also found that when researchers put hypertonic saline into affected ears one hour after the noise exposure, the saline drew the fluid out of the inner ear, the endolymphatic hydrops resolved, and the long-term inner ear nerve damage in the mice decreased.
“This is something we didn’t really know before,” Dr. Oghalai said. “This kind of optical imaging technology not only allowed us to develop a better understanding of hearing loss but also to develop a potential treatment for it.”
How Optical Coherence Tomography Works
A high-resolution imaging technique, OCT uses laser light in the near-infrared spectral range to produce high quality cross-sectional images. This noninvasive tool has been studied for use in interventional cardiology to diagnose coronary artery disease and has been adopted in the clinical field of ophthalmology to image the retina, which contains the eye’s sensory cells. Dr. Kozin said researchers in the field of otolaryngology hypothesize that OCT may also be used to image inner ear microanatomy while keeping the cochlear intact.
“Unlike the retina, which can be imaged by placing a noninvasive probe adjacent to the eye, the inner ear sensory cells aren’t readily imaged given their location within the temporal bone, making it challenging to harness OCT technology,” he said. “To date, investigators have devised novel ear-specific probes and procedural approaches in animal models to visualize and study the microanatomy of the inner ear.”
In Dr. Oghalai’s studies, his team focused the near-infrared light through a lens into the mouse’s ear. The light penetrated the eardrum through the bone that surrounds the cochlea, and then entered the bone. As the light hit these structures, some of it scattered, some was absorbed, and some was reflected back at an angle that allowed researchers to collect it again with their lens. “We collect what light gets backscattered and then compare it to the light we sent in,” Dr. Oghalai said. “And when you do that, you see a difference. That difference tells you what the structure is of the tissue it penetrated.”
Baran D. Sumer, MD, professor and chief of the division of head and neck oncology in the department of otolaryngology at the University of Texas Southwestern Medical Center in Dallas, said that OCT could someday be an incredible tool for looking noninvasively at physiologic disruption on a very small scale in the inner ear. “That would be game changing, because you would be able to potentially diagnose lesions of the brain and disruptions of nerves in the head, neck, and other areas, as well as scanning other kinds of small, delicate structures of the body,” he said. Dr. Sumer and his collaborators have used nanotechnology in developing a digital nanoprobe to decipher healthy tissue from cancerous tissue during surgery, an approach that might hold promise for otology tools.
Dr. Oghalai and his colleagues have built a device using OCT that’s made for use in humans and have been testing it in their clinic for the past few years, though he said it’s been a slow process involving a lot of software changes. “Building a device that works in a mouse that’s anesthetized is a lot different than building one that can be used in a patient, especially one who’s awake,” he said. “It has to work very fast so that we aren’t putting patients through too much of a long wait. And it has to give us meaningful images that we can use in a clinical setting.”
New Drug Therapies and Regenerative Medicine
Researchers are now also harnessing advances in various therapeutic arenas like gene therapy to try to reverse and potentially cure specific causes of hearing loss. For example, novel drugs may target specific gene mutations that cause hearing loss. According to Dr. Kozin, many basic science research studies have shown the ability of novel inner ear therapeutics to regenerate the inner ear in mouse models, with the hope that these regenerative therapeutics may one day be applied to hearing loss in humans. Novel medications, according to Dr. Kozin, may also give physicians the opportunity to think about treating patients at risk for hearing loss—in other words, treat hearing loss before it actually occurs.
An exciting and growing area of research over the past decade has shown us that a major cause of this hearing difficulty is loss of synapses between the inner ear hair cells and the nerve cells that connect to the brain. —Jeffrey Harris, MD, PhD
In addition to researching therapeutic drugs, investigators are actively researching delivery devices such as microneedles and hydrogels to make the human ear more accessible. “Given that sensory cells of the peripheral auditory pathway are challenging to access surgically, novel drug delivery devices will likely be necessary to deliver drugs in a fashion that doesn’t further damage the inner ear,” Dr. Kozin said.
The current standard of care in hearing loss primarily addresses the amplification of sounds. Therapeutics, however, could potentially repair an underlying condition and improve the clarity of sound for patients with hearing loss. This could change the standard of care considerably and improve the lives of patients, said Carl LeBel, PhD, a scientific fellow of the American Academy of Otolaryngology–Head and Neck Surgery and chief development officer at Frequency Therapeutics, a clinical-stage biotechnology company focused on restoring function in hearing loss through therapeutics.
“I believe it’s now abundantly clear that speech perception is the most impactful component of acquired sensorineural hearing loss,” Dr. LeBel said. He added that at a recent FDA patient-focused drug development meeting led by the Hearing Loss Association of America, patients’ chief complaints, when asked about the top two needs for a drug or a device, were trouble hearing when background noise is present and sounds being muffled. “It’s clear from this event that patients with hearing loss want to hear more clearly, suggesting that speech perception is the primary unmet medical need in this space,” he said.
Consequently, Frequency Therapeutics is studying drug therapy and small-molecule therapeutics in regenerative medicine to restore hearing function and enhance a patient’s ability to clearly understand speech. In October 2021, the company began a new Phase 2b study of FX-322, their lead hearing restoration candidate, which is designed to regenerate sensory hair cells in the cochlea. This clinical trial, their largest to date, is a randomized, placebo-controlled, multicenter study designed to evaluate the impact of FX-322 on speech perception, a clinical measure of sound clarity and understanding speech, in approximately 124 subjects with sensorineural hearing loss. The study will include subjects with hearing loss associated with either noise-induced or sudden sensorineural hearing loss. A variety of listening tests, including multiple measures of speech perception and pure tone thresholds, will be assessed. The treatment is a combination of two small molecules designed to address the underlying cause of sensorineural hearing loss by regenerating sensory hair cells through the activation of progenitor cells already present in the cochlea.
“To the best of our knowledge, our regenerative approach is unlike any other being taken in the hearing loss space,” Dr. LeBel said. “Our focus is on hair cell development, where we decode the signals that drive these cells, and we modulate those signals with combinations of small molecules. It’s the loss of these sensory hair cells that’s thought to be the primary consequence of acquired sensorineural hearing loss.”
Administered by intratympanic injection, FX-322 offered the first-ever evidence of hearing improvement in humans with a therapeutic candidate, according to Dr. LeBel. “Two clinical studies in which a single dose of FX-322 was administered have shown statistically significant and clinically meaningful improvements in speech perception,” he said. “In addition, in all FX-322 studies, this drug candidate was observed to be well tolerated, with no serious drug-related adverse effects.”
A Phase 3 trial will be the next step before seeking FDA approval. Given the significant unmet medical need in hearing loss, the FDA has granted FX-322 fast-track status.
The biopharmaceutical company Otonomy, which focuses on enabling drug therapies to reach their targets within the protected inner ear, is pursuing successful clinical trial results for two of its experimental drugs to treat tinnitus and hearing loss. Their potential treatment for tinnitus, OTO-313, is a formulation of a potent small molecule called gacyclidine, which is an NMDA receptor antagonist.
Dr. Harris said the idea behind gacyclidine is that it may block the overactive signaling from the hair cells to their nerve receptors, reducing or eliminating this overexcitation and, by doing so, treating tinnitus.
“OTO-313 also has a unique, proprietary formulation that provides sustained levels of drug into the inner ear, thereby providing a single course of treatment from a single, in-office administration of OTO-313 by the ENT physician,” Dr. Harris said. “This sustained drug delivery knowledge was a major part of the advance we made that led to the creation of Otonomy.”
The goal of these new imaging modalities is to better delineate inner ear microanatomy to understand the underlying causes of hearing loss. —Elliott D. Kozin, MD
OTO-313 for tinnitus is currently enrolling patients in a Phase 2 trial across the United States and Europe. This trial follows a successful Phase 1/2 trial that demonstrated OTO-313 to be well tolerated and provided proof-of-concept for effectiveness by showing decreased severity of tinnitus following a single treatment. The results have recently been published in Otology & Neurotology (2021;42:e1625-e1633). The results from the Phase 2 trial in mid-2022 should, if successful, advance into Phase 3 trials that would be used to file for FDA approval.
By contrast, Otonomy’s prospective hearing loss treatment, OTO-413, is a brain-derived neurotrophic factor (BDNF), which is a biologic or small protein. This endogenous protein is expressed in embryonic development, causing nerve cells to grow and connect to their target cells.
“OTO-413 targets the most common complaint among hearing loss patients: difficulty in hearing others speak in the background of everyday noise, or what’s termed speech-in-noise hearing difficulty,” Dr. Harris said. “An exciting and growing area of research over the past decade has shown us that a major cause of this hearing difficulty is loss of synapses between the inner ear hair cells and the nerve cells that connect to the brain.”
This loss of synapses between the sensory cells and the brain, or cochlear synaptopathy, results in the loss of important information being transmitted to the brain that would allow it to decipher speech from background sound. “OTO-413 is another unique sustained delivery formulation that delivers BDNF to the inner ear, causing the nerve cells to regrow lost or damaged synapses and re-attach to the hair cells,” Dr. Harris said.
OTO-413 recently completed its own Phase 1/2 trial showing that the doses tested in that study were well tolerated by patients and evaluating potential efficacy in the highest dose test. Based on these results, OTO-413 is currently enrolling a Phase 2a patient population. Otonomy expects to proceed to a Phase 2 trial by the end of 2022.
“We’ve seen over the past two decades the incredible advancement that can be made in saving people’s vision by the development of therapeutics to treat many common diseases that cause blindness,” Dr. Harris said. “I’m confident that is now the exciting path we’re on in the field of neurotology.”
Dr. Kozin believes it’s critical to keep up the momentum in understanding and treating the causes of sensorineural hearing loss with research funding. “It’s important to recognize that basic science studies that try to understand fundamental aspects of hearing physiology and causes of hearing pathology are equally as important to fund as the specific drugs that may one day provide inner ear regeneration.”
With no currently available FDA-approved medication for the treatment of sensorineural hearing loss and little knowledge about potential risks and side effects of emerging therapeutics, however, Dr. Kozin cautions that it’s best to counsel patients on options available today rather than instructing them to wait for new treatments. “I wouldn’t want to see a patient pass up currently available treatment and continue to have a decrement in quality of life due to hearing loss that could be alleviated today while waiting for a yet-to-be approved class of medications.”
Renée Bacher is a freelance medical writer based in Louisiana.