Could a drug prevent hearing loss from loud music and aging?

Researchers have found a gene that links deafness to cell death in the inner ear in humans -- creating new opportunities for averting hearing loss.

A person's hearing can be damaged by loud noise, aging and even certain medications, with little recourse beyond a hearing aid or cochlear implant.

But now, UCSF scientists have achieved a breakthrough in understanding what is happening in the inner ear during hearing loss, laying the groundwork for preventing deafness.

The research, published on Dec. 22, 2023, in the Journal of Clinical Investigation Insight, links animal studies on hearing loss with a rare type of inherited deafness in humans. In both cases, mutations to the TMTC4 gene trigger a molecular domino effect known as the unfolded protein response (UPR), leading to the death of hair cells in the inner ear.

Intriguingly, hearing loss from loud noise exposure or drugs such as cisplatin, a common form of chemotherapy, also stems from activation of the UPR in hair cells, suggesting that the UPR may underly several different forms of deafness.

There are several drugs that block the UPR -- and stop hearing loss -- in laboratory animals. The new findings make a stronger case for testing these drugs in people who are at risk of losing their hearing, according to the researchers.

"Millions of American adults lose their hearing due to noise exposure or aging each year, but it's been a mystery what was going wrong," said Dylan Chan, MD, PhD, co-senior author on the paper and director of the Children's Communication Center (CCC) in the UCSF Department of Otolaryngology. "We now have solid evidence that TMTC4 is a human deafness gene and that the UPR is a genuine target for preventing deafness."

How hair cells in the ear self-destruct

In 2014, Elliott Sherr, MD, PhD, director of the UCSF Brain Development Research Program and co-senior author of the paper, noticed that several of his young patients with brain malformations all had mutations to TMTC4. But laboratory studies of this gene soon presented a conundrum.

"We expected mice with TMTC4 mutations to have severe brain defects early on, like those pediatric patients, yet to our surprise, they seemed normal at first," Sherr said. "But as those animals grew, we saw that they didn't startle in response to loud noise. They had gone deaf after they had matured."

Sherr partnered with Chan, an expert on the inner ear, to look into what was happening to the mice, which looked like an accelerated version of age-related hearing loss in humans. They showed that mutations to TMTC4 primed hair cells in the ear to self-destruct, and loud noise did the same thing. In both cases, hair cells were flooded with excess calcium, throwing off the balance of other cellular signals, including the UPR.

But they found there was a way to stop this. ISRIB, a drug developed at UCSF to block the UPR's self-destruct mechanism in traumatic brain injury, prevented animals who were exposed to noise from going deaf.

The first adult human deafness gene

In 2020, scientists from South Korea, led by Bong Jik Kim, MD, PhD, connected Chan and Sherr's 2018 findings with genetic mutations they found in two siblings who were losing their hearing in their mid-20s. The mutations were in TMTC4 and matched what Chan and Sherr had seen in animals, although they were distinct from those in Sherr's pediatric neurology patients.

"It's rare to so quickly connect mouse studies with humans," Sherr said. "Thanks to our Korean collaborators, we could more easily prove the relevance of our work for the many people who go deaf over time."

Kim, an otolaryngologist at the Chungnam National University College of Medicine (Korea), facilitated the shipping of cells from those patients to UCSF. Sherr and Chan tested those cells for UPR activity and found that, indeed, this flavor of TMTC4 mutation turned on the destructive UPR pathway in a human context.

When Chan and Sherr mutated TMTC4 only in hair cells in mice, the mice went deaf. When they mutated TMTC4 in cells from individuals in the Korean family who hadn't gone deaf, and in laboratory human cell lines, the UPR drove the cells to self-destruct. TMTC4 was more than a deafness gene in mice -- it was a deafness gene in humans, too.

Translating a discovery to prevent deafness

Understanding TMTC4 mutations gives researchers a new way of studying progressive deafness, since it is critical for maintaining the health of the adult inner ear. The mutations mimic damage from noise, aging or drugs like cisplatin.

The researchers envision a future where people who must take cisplatin, or who have to be exposed to loud noises for their jobs, take a drug that dampens the UPR and keeps hair cells from withering away, preserving their hearing.

The science also suggests that the UPR could be targeted in other contexts where nerve cells become overwhelmed and die, including diseases long thought to be incurable, like Alzheimer's or Lou Gehrig's disease.

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An unexpected doorway into the ear opens new possibilities for hearing restoration

An international team of researchers has developed a new method to deliver drugs into the inner ear. The discovery was possible by harnessing the natural flow of fluids in the brain and employing a little understood backdoor into the cochlea. When combined to deliver a gene therapy that repairs inner ear hair cells, the researchers were able to restore hearing in deaf mice.

"These findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step towards using gene therapy to restore hearing in humans," said Maiken Nedergaard, MD, DMSc, senior author of the new study, which appears in the journal Science Translational Medicine.

Nedergaard is co-director of the Center for Translational Neuromedicine at University of Rochester and the University of Copenhagen. The study was the product of a collaboration between researchers at the two universities and a group led by Barbara Canlon, Ph.D. in the Laboratory of Experimental Audiology at the Karolinska Institute in Stockholm, Sweden.

The number of people worldwide predicted to have mild to complete hearing loss is expected to grow to around 2.5 billion by mid-century. The primarily cause is the death or loss of function of hair cells found in the cochlea -- which are responsible for relaying sounds to the brain -- due to mutations of critical genes, aging, noise exposure, and other factors.

While hair cells do not naturally regenerated in humans and other mammals, gene therapies have shown promise and in separate studies have successfully repaired the function of hair cells in neo-natal and very young mice. However, as both mice and humans age, the cochlea, already a delicate structure, becomes enclosed in temporal bone. At this point, any effort to reach the cochlea and deliver a gene therapy via surgery risks damaging this sensitive area and altering hearing.

In the new study, the researchers describe a little understood passage into the cochlea called the cochlear aqueduct. While the name conjures images of monumental stone architecture, the cochlear aqueduct is thin boney channel no larger than a single strand of hair. Suspected to play a role in balancing pressure in the ear, new study shows that that the cochlear aqueduct also acts as a conduit between the cerebrospinal fluid found in the inner ear and the rest of the brain.

Scientists are developing clearer picture of the mechanics of glymphatic system, the brain's unique process of removing waste first described by the Nedergaard lab in 2012. Because the glymphatic system pumps cerebrospinal fluid deep into brain tissue to wash away toxic proteins, researchers have been eyeing it as a potentially new way to deliver drugs into the brain, a major challenge in developing drugs for neurological disorders.

Researchers have also discovered that the complex movement of fluids driven by the glymphatic system extend to the eyes and the peripheral nervous system, including ear. The new study represented an opportunity to put the drug delivery potential of the glymphatic system to the test, while at the same time targeting a previously unreachable part of the auditory system.

Employing a number of imagining and modeling technologies, the researchers were able to develop a detailed portrait of how fluid from other parts of the brain flows through cochlear aqueduct and into the inner ear. The team then injected an adeno-associated virus into the cisterna magna, a large reservoir of cerebrospinal fluid found at the base of the skull. The virus found its way into the inner ear via the cochlear aqueduct, delivered a gene therapy that expresses a protein called vesicular glutamate transporter-3, which enable the hair cells to transmit signal and rescued hearing in adult deaf mice.

"This new delivery route into the ear may not only serve the advancement of auditory research, but also prove useful when translated to humans with progressive genetic-mediated hearing loss," said Nedergaard.

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Ludwig van Beethoven's genome sheds light on chronic health problems and cause of death

In 1802, Ludwig van Beethoven asked his brothers to request that his doctor, J.A. Schmidt, describe his malady -- his progressive hearing loss -- to the world upon his death so that "as far as possible at least the world will be reconciled to me after my death." Now, more than two centuries later, a team of researchers reporting in the journal Current Biology on March 22 have partially fulfilled his wish by analyzing DNA they lifted and pieced together from locks of his hair.

"Our primary goal was to shed light on Beethoven's health problems, which famously include progressive hearing loss, beginning in his mid- to late-20s and eventually leading to him being functionally deaf by 1818," said Johannes Krause from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

"We were unable to find a definitive cause for Beethoven's deafness or gastrointestinal problems," Krause says. "However, we did discover a number of significant genetic risk factors for liver disease. We also found evidence of an infection with hepatitis B virus in at latest the months before the composer's final illness. Those likely contributed to his death."

As commonly happens when people analyze DNA, the researchers uncovered another surprise. Beethoven's Y chromosome doesn't match that of any of five modern-day relatives carrying the same last name and sharing, on the basis of genealogical records, a common ancestor with Beethoven's paternal line. The finding points to an extramarital "event" somewhere over the generations on Beethoven's father's side.

"This finding suggests an extrapair paternity event in his paternal line between the conception of Hendrik van Beethoven in Kampenhout, Belgium in c.1572 and the conception of Ludwig van Beethoven seven generations later in 1770, in Bonn, Germany," says Tristan Begg, now at the University of Cambridge, U.K.

The idea for the work was conceived by Begg and study co-author William Meredith almost a decade ago. They were motivated by Beethoven's request for postmortem studies to describe his illness and make it public. In the new study, the team, also including Toomas Kivisild of Katholieke Universiteit Leuven in Belgium, relied on recent improvements in ancient DNA analysis; these improvements have enabled whole-genome sequencing from small quantities of historical hair.

First, they analyzed independently sourced locks of hair attributed to Beethoven, only five of which they confirmed came from the same European male. They deemed these five to be "almost certainly authentic" and used them to sequence Beethoven's genome to 24-fold genomic coverage.

Medical biographers had earlier suggested that Beethoven had many substantially heritable health conditions. But the researchers in this study couldn't find in his genome an explanation for Beethoven's hearing disorder or gastrointestinal problems. They did find that he was genetically predisposed to liver disease.

Further study of other DNA in his samples suggested that he also had a hepatitis B infection at least during the months leading up to his death. "Together with the genetic predisposition and his broadly accepted alcohol consumption, these present plausible explanations for Beethoven's severe liver disease, which culminated in his death," they write.

The researchers note that previous analyses suggesting that Beethoven had lead poisoning turned out to have been based on a sample that wasn't Beethoven's at all; instead, it came from a female. Future studies testing for lead, opiates, and mercury must be based on authenticated samples, they say.

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Can hearing loss be reversed? Research reveals clues that could regrow the cells that help us hear

Taking a bite of an apple is considered a healthy choice. But have you ever thought about putting in earplugs before your favorite band takes the stage?

Just like your future body will thank you for the apple, your future ears (specifically your cochlear hair cells) will thank you for protecting them. The most common cause of hearing loss is progressive because these hair cells -- the primary cells to detect sound waves -- cannot regenerate if damaged or lost. People who have repeated exposure to loud noises, like military personnel, construction workers, and musicians, are most at risk for this type of hearing loss. But, it can happen to anyone over time (even concert goers).

On the other hand, birds and fish can regenerate these hair cells, and now researchers at the Del Monte Institute for Neuroscience are getting closer to identifying the mechanisms that may promote this type of regeneration in mammals, as explained in research recently published in Frontiers in Cellular Neuroscience.

"We know from our previous work that expression of an active growth gene, called ERBB2, was able to activate the growth of new hair cells (in mammals), but we didn't fully understand why," said Patricia White, PhD, professor of Neuroscience and Otolaryngology at the University of Rochester Medical Center. The 2018 study led by Jingyuan Zhang, PhD, a postdoctoral fellow in the White lab at the time, found that activating the growth gene ERBB2 pathway triggered a cascading series of cellular events by which cochlear support cells began to multiply and activate other neighboring stem cells to become new sensory hair cells.

"This new study tells us how that activation is happening -- a significant advance toward the ultimate goal of generating new cochlear hair cells in mammals," said White.

Using single-cell RNA sequencing in mice, researchers compared cells with an overactive growth gene (ERBB2 signaling) with similar cells that lacked such signaling. They found the growth gene -- ERBB2 -- promoted stem cell-like development by initiating the expression of multiple proteins -- including SPP1, a protein that signals through the CD44 receptor. The CD44 receptor is known to be present in cochlear-supporting cells. This increase in cellular response promoted mitosis in the supporting cells, a key event for regeneration.

"When we checked this process in adult mice, we were able to show that ERBB2 expression drove the protein expression of SPP1 that is necessary to activate CD44 and grow new hair cells," said Dorota Piekna-Przybylska, PhD, a staff scientist in the White Lab and first author of the study. "This discovery has made it clear that regeneration is not only restricted to the early stages of development. We believe we can use these findings to drive regeneration in adults."

"We plan to further investigation of this phenomenon from a mechanistic perspective to determine whether it can improve auditory function after damage in mammals. That is the ultimate goal," said White.

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New tool to create hearing cells lost in aging

Hearing loss due to aging, noise and certain cancer therapy drugs and antibiotics has been irreversible because scientists have not been able to reprogram existing cells to develop into the outer and inner ear sensory cells -- essential for hearing -- once they die.

But Northwestern Medicine scientists have discovered a single master gene that programs ear hair cells into either outer or inner ones, overcoming a major hurdle that had prevented the development of these cells to restore hearing.

The study will be published in Nature May 4.

"Our finding gives us the us the first clear cell switch to make one type versus the other," said lead study author Jaime Garcia-Anoveros, professor of anesthesia, neurology and neuroscience at Northwestern University Feinberg School of Medicine. "It will provide a previously unavailable tool to make an inner or outer hair cell. We have overcome a major hurdle."

About 8.5 percent of adults aged 55 to 64 in the U.S. have disabling hearing loss. That increases to nearly 25 percent of those aged 65 to 74 and 50 percent of those who are 75 and older, reports the Centers for Disease Control.

Currently, scientists can produce an artificial hair cell, but it does not differentiate into an inner or outer cell, which provide different essential functions to produce hearing. The discovery is a major step towards developing these specific cells.

"It's like a ballet" as cells crouch and leap

The death of outer hair cells made by the cochlea are most often the cause of deafness and hearing loss. The cells develop in the embryo and do not reproduce. The outer hair cells expand and contract in response to the pressure of sound waves and amplify sound for the inner hair cells. The inner cells transmit those vibrations to the neurons to create the sounds we hear.

"It's like a ballet," Garcia-Anoveros says with awe as he describes the coordinated movement of the inner and outer cells. "The outers crouch and jump and lift the inners further into the ear.

"The ear is a beautiful organ. There is no other organ in a mammal where the cells are so precisely positioned. (I mean, with micrometric precision). Otherwise, hearing doesn't occur."

The master gene switch Northwestern scientists discovered that programs the ear hair cells is TBX2. When the gene is expressed, the cell becomes an inner hair cell. When the gene is blocked, the cell becomes an outer hair cell. The ability to produce one of these cells will require a gene cocktail, Garcia-Anoveros said. The ATOH1 and GF1 genes are needed to make a cochlear hair cell from a non-hair cell. Then the TBX2 would be turned on or off to produce the needed inner or outer cell.

The goal would be to reprogram supporting cells, which are latticed among the hair cells and provide them with structural support, into outer or inner hair cells.

"We can now figure out how to make specifically inner or outer hair cells and identify why the later are more prone to dying and cause deafness," Garcia-Anoveros said. He stressed this research is still in the experimental stage.

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Which speaker are you listening to? Hearing aid of the future uses brainwaves to find out

 In a noisy room with many speakers, hearing aids can suppress background noise, but they have difficulties isolating one voice -- that of the person you're talking to at a party, for instance. KU Leuven researchers have now addressed that issue with a technique that uses brainwaves to determine within one second whom you're listening to.

Having a casual conversation at a cocktail party is a challenge for someone with a hearing aid, says Professor Tom Francart from the Department of Neurosciences at KU Leuven: "A hearing aid may select the loudest speaker in the room, for instance, but that is not necessarily the person you're listening to. Alternatively, the system may take into account your viewing direction, but when you're driving a car, you can't look at the passenger sitting next to you."

Researchers have been working on solutions that take into account what the listener wants. "An electroencephalogram (EEG) can measure brainwaves that develop in response to sounds. This technique allows us to determine which speaker someone wants to listen to. The system separates the sound signals produced by different speakers and links them to the brainwaves. The downside is that you have to take into account a delay of ten to twenty seconds to get it right with reasonable certainty."

Artificial intelligence to speed up the process

A new technique makes it possible to step up the pace, Professor Alexander Bertrand from the Department of Electrical Engineering at KU Leuven continues: "Using artificial intelligence, we found that it is possible to directly decode the listening direction from the brainwaves alone, without having to link them to the actual sounds."

"We trained our system to determine whether someone is listening to a speaker on their left or their right. Once the system has identified the direction, the acoustic camera redirects its aim, and the background noise is suppressed. On average, this can now be done within less than one second. That's a big leap forward, as one second constitutes a realistic timespan to switch from one speaker to the other."

From lab to real life

However, it will take at least another five years before we have smart hearing aids that work with brainwaves, Professor Francart continues. "To measure someone's brainwaves in the lab, we make them wear a cap with electrodes. This method is obviously not feasible in real life. But research is already being done into hearing aids with built-in electrodes."

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Gene discovery in fruit flies 'opens new doors' for hearing loss cure in elderly

Scientists at UCL have discovered sets of regulatory genes, which are responsible for maintaining healthy hearing. The finding, made in fruit flies, could potentially lead to treatments for age-related hearing loss (ARHL) in humans.

Globally one third of people (1.23 billion people) aged over 65 experience hearing impairment, and while there are thought to be more than 150 candidate genes which may affect hearing loss, there is no unified view on how to use these to develop novel preventive or curative hearing loss therapies.

In the study, published in Scientific Reports, researchers at the UCL Ear Institute assessed the hearing ability of the common fruit fly (Drosophila melanogaster) across its life span (around 70 days*), to see if their hearing declines with age.

The fruit fly is a powerful model in biology and its ear shares many molecular similarities with the ears of humans, which make it an ideal tool for the study of human hearing loss. However, so far, no study had assessed the fruit flies' hearing across their life course.

Using advanced biomechanical, neurophysiological and behavioural techniques**, the researchers found that the antennal ears of fruit flies also display ARHL with nearly all measures of sensitive hearing starting to decline after 50 days of age.

With this knowledge, the researchers turned their interest to the time before flies developed ARHL: they wanted to know if there were any 'age-variable' genes in the flies' Johnston's Organ (their 'inner ear'), which have kept the ears healthy for 50 days of their lives.

Using a combination of molecular biology, bioinformatics and mutant analysis, the researchers identified a new set of transcriptional regulator genes: these are so called 'homeostasis genes', meaning they are the genetic actuators, so they control the activity which keeps the ear sensitive.

For researchers, one of the principle advantages of the fruit fly model is that it allows for easily testing the roles of individual genes by either increasing their function (overexpression) or silencing them (RNAi interference). Exploiting these tools, researchers also found that manipulating some of the homeostasis genes could prevent the flies from getting ARHL.

Lead author Professor Joerg Albert (UCL Ear Institute) said: "While many studies have been conducted into the hearing function of fruit flies, ours is the first to look at the mechanistic and molecular detail of their auditory life course.

"Our twin discoveries that fruit flies experience age-related hearing loss and that their prior auditory health is controlled by a particular set of genes, is a significant breakthrough. The fact that these genes are conserved in humans will also help to focus future clinical research in humans and thereby accelerate the discovery of novel pharmacological or gene-therapeutic strategies.

"Building on our findings from Drosophila, we have already started a follow-up drug discovery project designed to fast-track novel treatments for human ARHL."

Dr Ralph Holme, Executive Director of Research at Action on Hearing Loss, said: 'We urgently need to find effective treatments able to prevent or slow the loss of hearing as we age.

"Hearing loss affects 70% of people aged over 70 years old, cutting people off from friends and family.

"Action on Hearing Loss is proud to have been able to support this exciting research that has identified genes involved in maintaining hearing.

"It not only advances our understanding of why hearing declines with age, but importantly also opens the door to the future development of treatments to prevent it."

*At 25 degrees, one day for a fruit fly is equivalent (approximately) to one year for a human.

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How hearing loss in old age affects the brain

If your hearing deteriorates in old age, the risk of dementia and cognitive decline increases. So far, it hasn't been clear why. A team of neuroscientists has examined what happens in the brain when hearing gradually deteriorates: key areas of the brain are reorganized, and this affects memory.

Daniela Beckmann, Mirko Feldmann, Olena Shchyglo and Professor Denise Manahan-Vaughan from the Department of Neurophysiology of the Medical Faculty worked together for the study.

When sensory perception fades

The researchers studied the brain of mice that exhibit hereditary hearing loss, similar to age related hearing loss in humans. The scientists analysed the density of neurotransmitter receptors in the brain that are crucial for memory formation. They also researched the extent to which information storage in the brain's most important memory organ, the hippocampus, was affected.

Adaptability of the brain suffers

Memory is enabled by a process called synaptic plasticity. In the hippocampus, synaptic plasticity was chronically impaired by progressive hearing loss. The distribution and density of neurotransmitter receptors in sensory and memory regions of the brain also changed constantly. The stronger the hearing impairment, the poorer were both synaptic plasticity and memory ability.

"Our results provide new insights into the putative cause of the relationship between cognitive decline and age-related hearing loss in humans," said Denise Manahan-Vaughan. "We believe that the constant changes in neurotransmitter receptor expression caused by progressive hearing loss create shifting sands at the level of sensory information processing that prevent the hippocampus from working effectively," she adds.

From Science Daily