John Brigande provides commentary: Hearing in the mouse of Usher

Oregon Health & Science University

The March issue of Nature Biotechnology brings together a set of articles that provide an overview of promising RNA-based therapies and the challenges of clinical validation and commercialization. In his News and Views essay, “Hearing in the mouse of Usher,” John V. Brigande, Ph.D., provides commentary on two studies in the issue that report important progress in research on gene therapy for the inner ear.

One in eight people in the United States aged 12 years or older has hearing loss in both ears. That figure suggests that, if you don’t have hearing loss, you likely know someone who does. Worldwide, hearing loss profoundly interferes with life tasks like learning and interpersonal communication for an estimated 32 million children and 328 million adults worldwide. Inherited genetic mutations cause about 50 percent of these cases.

The challenge in developing gene therapy for the inner ear isn’t a lack of known genes associated with hearing loss, but a lack of vectors to deliver DNA into cells. Brigande, associate professor of otolaryngology and cell, developmental, and cancer biology at the OHSU School of Medicine, provides perspective on companion studies that demonstrate adeno-associated viral vectors as a potent gene transfer agent for cochlear cell targets.

The first study demonstrates safe and efficient gene transfer to hair cells of the mouse inner ear using a synthetic adeno-associated viral vector that promises to be a powerful starting point for developing appropriate vectors for use in the human inner ear. The second study demonstrates that a single neonatal treatment with this viral vector successfully delivers a healthy gene to the inner ear to achieve unprecedented recovery of hearing and balance in a mouse model of a disease called Usher syndrome. Individuals with Usher syndrome type 1c are born deaf and with profound balance issues and experience vision loss by early adolescence. The research teams were led by scientists from the Harvard School of Medicine.

Brigande sees these new studies as potentially spurring investment and kickstarting the development of new approaches to correct a diverse set of deafness genes. 

Hearing Restoration Project consortium member John V. Brigande, Ph.D., is a developmental neurobiologist at the Oregon Hearing Research Center. He also teaches in the Neuroscience Graduate Program and in the Program in Molecular and Cellular Biology at the Oregon Health & Science University. This blog was reposted with the permission of Oregon Health & Science University.

Second Cause of Hidden Hearing Loss Identified

By Michigan Medicine - University of Michigan

Some people can pass a hearing test but have trouble understanding speech in a noisy environment. New research identifies a new mechanism for this condition just years after its discovery. Credit: Michigan Medicine

Patients who complain they can't hear their friends at a noisy restaurant, but pass a hearing test in their doctor's office, may be describing hidden hearing loss.

Now, less than six years since its initial description, scientists have made great strides in understanding what hidden hearing loss is and what causes it. In research published in Nature Communications, University of Michigan researchers report a new unexpected cause for this auditory neuropathy, a step toward the eventual work to identify treatments.

"If people can have hidden hearing loss for different reasons, having the ability to make the right diagnosis of the pathogenesis will be critical," says author Gabriel Corfas, Ph.D., director of the Kresge Hearing Research Institute at Michigan Medicine's Department of Otolaryngology -- Head and Neck Surgery.

Corfas published the research with co-author Guoqiang Wan, now with Nanjing University in China. They discovered using mice that disruption in the Schwann cells that make myelin, which insulates the neuronal axons in the ear, leads to hidden hearing loss. This means hidden hearing loss could be behind auditory deficits seen in acute demyelinating disorders such as Guillain-Barré syndrome, which can be caused by Zika virus.

Corfas and Wan used genetic tools to induce loss of myelin in the auditory nerve of mice, modeling Guillain-Barré. Although the myelin regenerated in a few weeks, the mice developed a permanent hidden hearing loss. Even after the myelin regenerated, damage to a nerve structure called the heminode remained.

Synapse loss versus myelin disruption

When the ear is exposed to loud noises over time, synapses connecting hair cells with the neurons in the inner ear are lost. This loss of synapses has previously been shown as a mechanism leading to hidden hearing loss.

In an audiologist's quiet testing room, only a few synapses are needed to pick up sounds. But in a noisy environment, the ear must activate specific synapses. If they aren't all there, it's difficult for people to make sense of the noise or words around them. That is hidden hearing loss, Corfas says.

"Exposure to noise is increasing in our society, and children are exposing themselves to high levels of noise very early in life," Corfas says. "It's clear that being exposed to high levels of sound might contribute to increases in hidden hearing loss."

The newly identified cause -- deficiency in Schwann cells -- could occur in individuals who have already had noise exposure-driven hidden hearing loss as well. "Both forms of hidden hearing loss, noise exposure and loss of myelin, can occur in the same individual for an additive effect," Corfas says.

Previously, Corfas' group succeeded in regenerating synapses in mice with hidden hearing loss, providing a path to explore for potential treatment.

While continuing this work, Corfas started to investigate other cells in the ear, which led to uncovering the new mechanism.

There are no current treatments for hidden hearing loss. But as understanding of the condition improves, the goal is for the research to lead to the development of drugs to treat it.

"Our findings should influence the way hidden hearing loss is diagnosed and drive the future of clinical trials searching for a treatment," Corfas says. "The first step is to know whether a person's hidden hearing loss is due to synapse loss or myelin/heminode damage."

Materials provided by Michigan Medicine - University of Michigan. Co-author Guoqiang Wan, Ph.D., was a 2014 Emerging Research Grants recipient funded by the Wes Bradley, M.D. Memorial Grant.

We need your help in funding the exciting work of hearing and balance scientists.

To donate today to support HHF's groundbreaking research, please visit hhf.org/donate.

Celebrating Hearing Innovations

By Frankie Huang

On Feb. 25, Hearing Health Foundation is celebrating International Cochlear Implant Day to raise awareness of this life-changing technology. Cochlear implants greatly enhance the lives of individuals with severe to profound hearing loss and individuals who don’t benefit from the use of hearing aids. Did you know that as of November 2012, there are 324,000 cochlear implants in use worldwide, and that number is growing daily!

Cochlear implants (CI) are electronic medical devices that are implanted via a surgical procedure. Although implants replace the function of the damaged inner ear, it is important to remember that CIs do not restore normal hearing but work by bypassing damaged structures in the inner ear and stimulating the auditory nerve. This sends signals to the brain, allowing the user to perceive sounds.

Researchers found that children 5 years or older with bilateral severe or profound hearing loss who are implanted with CIs have better speech perception and development over time than children treated with hearing aids. In addition, children with profound hearing loss who used CIs showed greater development of preverbal behavior than those using hearing aids.

Other researchers found that children receiving CIs before 24 months of age greatly benefit in terms of their overall language development. Levels of spoken language in children implanted before age 24 months were on par with their typical hearing peers by age 4.5, but those implanted after age 24 months did not “catch up” with hearing peers by age 4.5. It’s important to note the study didn’t evaluate language development or ongoing delays after age 4.5.

HHF is proud to have supported research in the 1970s that led to the development of cochlear implants. Since then the technology has continued to evolve and improve in order to increase the benefits yielded from having a cochlear implant and to reduce risks associated with an invasive surgical procedure. By further improving the design and the function of CIs, researchers may find a way to maximize all the possible benefits for the patient, to preserve residual hearing, and to improve the health of the inner ear.

If you’re interested in funding research related to hearing loss technology,
please consider donating today at hhf.org/donate or contact us at development@hhf.org.

When It's Not Just Hearing Loss

By Morgan Leppla & Laura Friedman

This year Autism Sunday, an international day to raise awareness of autism spectrum disorder (ASD), is on Feb. 12.

Did you know that one third or more of pediatric hearing loss cases overlap with another condition? This may sometimes be ASD, making treatment and management of co-occurring conditions a challenge.

In a 2007 report in the Journal of Deaf Studies and Deaf Education, British researcher Lindsay Edwards, Ph.D., cites an estimate that 30 to 40 percent of children with hearing loss have co-occurring conditions that could prohibit them from forming language, speech, and sociocognitive skills. But despite this large percentage, there is little research on hearing loss that occurs with other disorders. What research there is has shown the benefit of cochlear implantation for children with additional needs (such as physical or learning disabilities), and the difficulties of language acquisition and development for 3-year-olds with developmentally related conditions such as ASD, cerebral palsy, or Down syndrome.

One silver lining is that the fact that 30 to 40 percent of pediatric hearing loss may occur with other conditions may prove helpful in predicting future disorders. A July 2016 Autism Research paper suggests that a noninvasive measure of otoacoustic emissions in the inner ear—a common hearing test for infants, who are preverbal—may help identify the risk of ASD at an early age, accelerating treatment. Study author Anne Luebke, Ph.D., of University of Rochester Medical School, found that children with ASD often have trouble hearing a frequency range (1–2 kHz) that is important for understanding speech. The range includes sounds for the meaning-conveying consonants S-, H-, and F-.

Scientific conclusions can help shape future research, but cannot illustrate daily life for families with children with co-occurring conditions. Dual diagnoses make unlocking any child’s learning style challenging, but reviving research and upgrading professional training are essential tools in order to advocate for and successfully educate children with co-occurring conditions.

If you’re interested in funding research related to diagnosing and treating co-occuring disorders, such as hearing loss and autism, please consider donating today: hhf.org/donate or contact us at development@hhf.org.

This blog was adapted from an article original appearing in Hearing Health magazine’s Fall 2016 issue. For references in this story, see hhf.org/fall2016_references.

A Fight Against Cancer Is a Fight Against Hearing Loss

By Frankie Huang

In honor of World Cancer Day on February 4, Hearing Health Foundation (HHF) wants to raise awareness of the connection between cancer and hearing loss. Every year, 8.2 million people worldwide die from cancer, a disease that is responsible for 13% of all deaths globally.

Depending on the type of cancer, patients that undergo chemotherapy are sometimes required to take certain drugs that could cause many side effects, including hearing loss. Cisplatin is a chemotherapy drug that is often used to treat testicular, bladder, ovarian and lung cancers. However, an excessive dose of cisplatin can be ototoxic (toxic to the ear), which could lead to temporary or permanent hearing loss.

One study suggested that cisplatin-induced hearing loss is generally bilateral (both ears) and irreversible. The study also found that cisplatin accumulates in cochlear tissue, preventing the cochlea from flushing out toxins. The same researchers found that patients receiving doses of cisplatin between 150-225 mg/m2 showed some degree of hearing loss. For testicular cancer patients, more than 50% of the patients that took cisplatin in doses greater than 400 mg/m2 had permanent hearing loss. Hearing loss may occur within hours or days after the treatment, or hearing may gradually decline after completion of therapy. After following up more than two years later, the study authors found that 44% of patients who took cisplatin had significant hearing loss.

In another recent study, researchers found that the WFS1 gene is associated with cisplatin-related ototoxicity; the heavier the dose, the more severe the hearing loss. Also, a mutation of the WFS1 gene results in Wolfram syndrome, a disorder with deafness as a major symptom.

As of now, there are no safe and protective agents against cisplatin, but scientists are hard at work to find a protective agent that would eliminate the negative side effects of cisplatin. Currently there’s a solution for children that are receiving cisplatin-based chemotherapy: The use of sodium thiosulfate may minimize or protect children and adolescents against cisplatin-induced hearing loss. HHF hopes more preventative therapies and cures for hearing loss can be discovered for all cisplatin-treated patients.

Interested in funding research in this area? Email us at development@hhf.org.

Music-Induced Hearing Loss: What Do College Students Know?

By Frankie Huang

Music-induced hearing loss (MIHL) is a result from listening to music that exceeds 85 decibels for prolonged periods of time. A decibel, or dB, is a unit to measure sound intensity, and 85 dB is roughly equivalent to the sound of heavy city traffic. Our listening devices and preferred listening levels are the leading cause for MIHL. For example, when you’re working out at the gym and you up the volume of your music to 100% to drown out the music the gym is broadcasting, you are putting yourself at risk for permanent hearing loss.

The frequent use of these devices to listen to music and watch videos typically requires the use of headphones, increasing the risk of MIHL. Portnuff, Figor, and Arehart (2011) found that a person should only use their listening devices for no more than 4 hours per day at 70% volume, or 90 minutes per day at 80% volume.

In a recent study, researchers measured college students’ knowledge on the proper use of listening devices and the effects of listening to music at high volumes. It was found that prolonged use of these devices coupled with loud preferred listening levels is higher in males than in females, with males being less aware of safe listening habits and were more likely to exceed the recommended daily limit. The study also found that female students were more conscious of these limits and more knowledgeable about the maximum listening levels per day, compared with their male counterparts. Furthermore, younger students (freshmen) were less aware of safe listening levels compared with older students who were sophomores.

The use of certain headphones can also increase the risk of MIHL. Among college students, in-ear headphones (e.g., earbuds) are more commonly used than over-the-ear, noise-canceling headphones, and in-ear headphones are associated with a higher risk of MIHL. The biggest difference between in-ear and over-the-ear headphone users was the individual’s listening levels: The study found that in-ear headphone users preferred to listen at a higher volume, while over-the-ear headphone users favored a lower volume because the noise-canceling features meant ambient noise was less of an issue.

Headphone users tend to increase the volume if they can’t block out environmental noises. New York City, for example, is usually noisy so individuals are more likely to listen to their music at a higher volume, which is putting individuals at a greater risk of MIHL. There’s also a greater preference for in-ear headphones between males and females. According to the studies, 52.8% of males believed that in-ear headphones delivered better sound than over-the-ear headphones, compared with 46.4% of females.

Overall, the study suggested that individuals should refrain from listening to music and watching videos at the maximum volume for an extensive amount of time. However, if there’s too much background noise, and it's a distraction, the individual should only increase the volume to 80% of the maximum for no more than 90 minutes daily. In addition, education about the risks of hearing loss and how to prevent it is important, including how noise-canceling headphones drown out environmental noises so the wearer can enjoy music on their personal devices at safer levels.

Hearing loss is irreversible, so investing in a quality headphone that can reduce the risk of MIHL is priceless.

References

Berg, Abbey L. et al. Music-Induced Hearing Loss:What Do College Students Know?. 43rd ed. 2016. Web. 12 Dec. 2016.

http://www.asha.org/uploadedFiles/ASHA/Publications/cicsd/2016F-Music-Induced-Hearing-Loss.pdf

Your Support Is Needed!

Hair cell regeneration is a plausible goal for eventual treatment of hearing and balance disorders.

The question is not if we will regenerate hair cells in humans, but when.  

However, we need your support to continue this vital research and find a cure!

Please make your gift today.

The HRP Shifts Gears for Greater Impact

By Peter Barr-Gillespie, Ph.D.

It’s remarkable to me that the Hearing Restoration Project (HRP) is five years old! While the past five years revealed that regeneration of sensory hair cells is more complex than anticipated, our scientists have nonetheless made significant progress. Several notable HRP research projects supported by Hearing Health Foundation (HHF) were published in 2016, and more are on the way.

Financial investment in the HRP is crucial for our success. Through the HRP, HHF supports promising innovative research areas that due to the lack of available funds are not adequately financed by other agencies. We continue to acquire large-scale genomics datasets, and the more we generate the more valuable they all are—comparing the results from different types of experiments is a key approach of the HRP.

In 2017 we will see a change in the way the HRP conducts its research. At our HRP meeting this past November, the consortium updated its research methods for the upcoming year, choosing to focus and devote more resources on two promising, major experimental strategies. This is a shift from the approach over the past five years, when the HRP followed various independent paths to understanding hair cell regeneration.

The first project will use “single-cell sequencing” experiments, which will reveal the molecular processes of hair cell regeneration in chicks and fish with unprecedented resolution. Single-cell methods allow us to examine thousands of genes in hundreds of individually isolated supporting cells, some of which are responding to hair cell damage.

With these voluminous datasets, we will then describe the succession of molecular changes needed to regenerate hair cells. Results from these experiments will be compared with similar experiments examining hair cell damage in mice, which like all mammals, including humans, do not regenerate hair cells.

The second project will examine whether epigenetic DNA modification (the inactivation of genes by chemical changes to the DNA) is why mice supporting cells are unable to transform into hair cells after damage to the ear. Our existing data suggests this is the case, and so a strategy for hearing restoration may involve the reversal of these epigenetic modifications.

The first project will allow us to identify the genes involved, and the second project will help us understand how to effectively manipulate those genes despite their DNA modifications—and to biologically restore hearing.

The consortium approach funded by HHF provides a unique opportunity; the collaboration of 15 outstanding hearing investigators will lead to results far more quickly than traditional projects that rely on a single investigator. All HRP investigators plan projects and interpret data arising from them, allowing us to collectively utilize our 200-plus years of experience we have studying the ear.

HHF has been able to increase HRP funding for 2017 compared with 2016—for this I am grateful. However, there are several research needs unmet. Increased funding levels would speed our deeper understanding of hair cell regeneration, which will ultimately lead us to find therapies to treat human hearing loss and tinnitus.

Most of all, we are looking to add additional scientists to HRP labs to increase productivity and significantly accelerate research progress. There is also an urgent need for more “bioinformatics” scientists to thoroughly examine our data and identify common threads buried deep within our results. In addition, the HRP has research projects that have been placed on hold until funding is found for them.

We are excited about the coming year’s planned research, and eagerly await the results. On behalf of myself and the other scientists who make up the HRP, I thank you for your investment and interest in our work. I look forward to giving you further updates.

HRP scientific director Peter Barr-Gillespie, Ph.D., is the associate vice president for Basic Research and a professor of otolaryngology at the Oregon Hearing Research Center, and a senior scientist at the Vollum Institute, all at Oregon Health & Science University. 

We need your help in funding the exciting work of hearing and balance scientists.

To donate today to support HHF's groundbreaking research,

please visit hhf.org/donate.

New Insights Into Age-Related Hearing Loss

By Ruili Xie, Ph.D.

Age-related hearing loss (ARHL), also known as presbycusis, is one of the most prevalent health conditions affecting older adults. The leading cause of ARHL is generally attributed to damage in the ear during aging, which include the loss of the inner ear’s sensory hair cells and spiral ganglion cells (SGCs).  

Hair cells act like antennae for the auditory system to receive sound information from the environment. SGCs are the nerve cells that connect the ear and the brain, with their peripheral branches receiving sound information from hair cells, and their central branches forming the auditory nerve to pass information to the brain. Recent studies showed that the terminals (endpoints) of SGC peripheral branches are vulnerable and can be damaged during aging, which are thought to be the primary cause of ARHL.    

However, the majority (over 70 percent) of SGC peripheral terminals survive normal aging. It is unclear whether, with age, sound information is reliably transmitted through the surviving SGCs to the brain; and if not, how this may contribute to ARHL.

One particular point of interest lies in the terminals of the SGC central branches (the auditory nerve synapses) that activate their target neurons in the brain. Deterioration in the information flow at these synapses with age would reduce sensory input to the brain and lead to ARHL.

For the first time, Dr. Paul B. Manis and I have found that the transmission of information from SGCs to their target neurons in the cochlear nucleus (the first auditory station in the brain) is compromised in aged mice with ARHL. The transmission process deteriorates due to abnormal calcium signaling at the central terminals of the SGCs. The study not only proposes a novel brain mechanism that underlies ARHL, but also provides new strategies in developing future clinical treatments.

Ruili Xie, Ph.D., a 2009 and 2010 Emerging Research Grants recipient, is an assistant professor in the Department of Neuroscience at the University of Toledo, in Ohio.The study “Synaptic Transmission at the Endbulb of Held Deteriorates During Age-Related Hearing Loss” appeared in The Journal of Physiology on Sept. 13, 2016.

We need your help supporting innovative hearing and balance science through our Emerging Research Grants program. Please make a contribution today.

Educators Must Address Diabetes-Related Hearing Loss

By Susan Weiner, MS, RDN, CDE, CDN and Joanne Rinker, MS, RD, CDE, LDN

Hearing loss may not be commonly thought of as a complication of diabetes. How did you become interested in the condition?

As a diabetes educator, when I think of diabetes complications, I think of kidney, eye, heart and nerve damage. What I don’t think about is hearing loss. In 2012, a colleague asked me what screenings I do for my patients to determine if they have hearing loss. I realized I did nothing because hearing loss really was never on my radar. Then she asked me to think about how a patient who has diabetes might feel if they also had trouble hearing. I started to think about how hearing loss can not only make life more difficult, but could also lead to depression. For a diabetes patient who is already dealing with the pressures of a complicated disease, adding hearing impairment to the list of stressors would be devastating. So, I decided that this was something worth discussing with other diabetes educators.

How common is hearing loss among people with diabetes?

I did some research, and it turns out that nearly 26 million people in the United States have diabetes, and an estimated 36 million people have some type of hearing loss (17%). NIH has found that hearing loss is twice as common among people with diabetes as among those who don’t have the disease. Also, of the 79 million adults thought to have prediabetes, the rate of hearing loss is 30% higher than in those with normal blood sugar levels.

Research suggests that diabetes may lead to hearing loss by damaging the nerves and blood vessels of the inner ear. Autopsy studies of patients with diabetes have shown evidence of such damage.

A recent study from Handzo and colleagues found that women between the ages of 60 and 75 years with well-controlled diabetes had better hearing than women with poorly controlled diabetes, with hearing levels similar to those of women of the same age without diabetes. The study also showed significantly worse hearing in all women younger than 60 years with diabetes, even when the disease is well controlled.

Additionally, a study by Bainbridge and colleagues showed that 54% of people with diabetes had at least mild hearing loss in their ability to hear high-frequency tones, compared with 32% of those with no history of diabetes. And 21% of participants with diabetes had at least mild hearing loss in their ability to hear low- to mid-frequency tones, compared with 9% of those without diabetes.

People with diabetes are 2.3 times more likely to have mild hearing loss, defined as having trouble hearing words spoken in a normal voice from more than 3 feet away. But the effects of hearing loss go beyond the ability to detect sound. Hearing loss is shown to lead to sadness and depression increasing with severity of hearing loss; worry and anxiety, including periods of a month or longer when the patient reports feeling worried, tense or anxious; paranoia (“people get angry at me for no reason”); less social activity; and emotional turmoil and insecurity.

What can diabetes educators do to help patients with hearing loss?

Encourage diabetes patients to be screened routinely for hearing loss, just as they are for eye and kidney problems. Those with mild to severe impairment should be referred to an audiologist for more intense screening and treatment.

Treatment for hearing loss will typically start with a hearing aid. Often this will alleviate the problem. In about 10% of the population, medication may also be necessary, but most hearing loss is corrected with the introduction of a hearing aid. With improved hearing, patients will also likely experience increased alertness; improved job performance, memory and mood; less loneliness, fatigue, tension, stress, negativism and anger; better relationships and feelings about themselves; and greater independence and security — improved overall quality of life.

The bottom line is that diabetes educators must remember to add this to their diabetes education curriculum. They should know the resources in their area and have a process for referring patients to an audiologist who can do more extensive screenings as well as order and fit patients for hearing aids. Lastly, they should follow up with patients with hearing loss about overall quality of life. I am sure they will surprised how much adding this one aspect of care can benefit the lives of their patients.

References:

• Bainbridge KE, et al. Ann Intern Med. 2008;149(1):1-10.

• Handzo D, et al. Effect of diabetes on hearing loss. Presented at: Triological Society 2012 Combined Sections Meeting. Miami Beach, Fla.; Jan. 26-28, 2012.

• National Academy on an Aging Society. Hearing loss: a growing problem that affects quality of life. 1999. Available at: http://ihcrp.georgetown.edu/agingsociety/pdfs/hearing.pdf

This blog post orginally appeared on Healio.com on March 1, 2016. 

Joanne Rinker, MS, RD, CDE, LDN, is Senior Director for Community Health Improvement at Population Health Improvement Partners and the 2013 American Association of Diabetes Educators (AADE) Diabetes Educator of the Year. She has been elected to the AADE Board of Directors 2015-2018. She can be reached at jorinker@gmail.com.

Susan Weiner, MS, RDN, CDE, CDN, is the 2015 AADE Diabetes Educator of the Year and author of The Complete Diabetes Organizer and Diabetes 365 Tips For Living Well. She is the owner of Susan Weiner Nutrition PLLC and is the Endocrine Today Diabetes in Real Life column editor. She can be reached at susan@susanweinernutrition.com.