Novel Drug-Delivery Method to the Inner Ear

By Gary Polakovic, USC News

Researchers have developed a new approach to be able to repair cells deep inside the ear. The study, conducted by scientists at University of Southern California (USC) and Harvard University, demonstrates a novel way for a future drug to zero in on damaged nerves and cells inside the ear.

Credit: Matthew Pla Savino/USC News

“What’s new here is we figured out how to deliver a drug into the inner ear so it actually stays put and does what it’s supposed to do, and that’s novel,” says Charles E. McKenna, Ph.D., a corresponding author for the study and chemistry professor at the USC Dornsife College of Letters, Arts, and Sciences.

“Inside this part of the ear, there’s fluid constantly flowing that would sweep dissolved drugs away, but our new approach addresses that problem. This is a first for hearing loss and the ear,” McKenna adds. “It’s also important because it may be adaptable for other drugs that need to be applied within the inner ear.”

The paper was published April 4 in the journal Bioconjugate Chemistry. The authors include lead researcher Judith S. Kempfle, Ph.D., a 2011 and 2012 Emerging Research Grants scientist, as well as Hearing Restoration Project member Albert Edge, Ph.D., both at Harvard Medical School and The Eaton-Peabody Laboratories in Boston.

There are caveats. The research was conducted on animal tissues in a petri dish. It has not yet been tested in living animals or humans. Yet the researchers are hopeful given the similarities of cells and mechanisms involved. McKenna says since the technique works in the laboratory, the findings provide “strong preliminary evidence” it could work in living creatures. They are already planning the next phase involving animals and hearing loss.

The study breaks new ground because researchers developed a novel drug-delivery method. Specifically, it targets the cochlea, a snail-like structure in the inner ear where sensitive cells convey sound to the brain. Hearing loss occurs due to aging or exposure to noise at unsafe levels. Over time, hair-like sensory cells and bundles of neurons that transmit their vibrations break down, as do ribbon-like synapses, which connect the cells.

The researchers designed a molecule combining 7,8-dihydroxyflavone, which mimics a protein critical for development and function of the nervous system, and bisphosphonate, a type of drug that sticks to bones. This pairing delivered the breakthrough solution, the researchers say, as neurons responded to the molecule and regenerated synapses in mouse ear tissue. This led to the repair of the hair cells and neurons, which are essential to hearing.

“We’re not saying it’s a cure for hearing loss,” McKenna says. “It’s a proof of principle for a new approach that’s extremely promising. It’s an important step that offers a lot of hope.” Hearing loss affects two thirds of people over 70 years and 17 percent of all adults in the United States, and it is expected to nearly double in 40 years.

This is adapted from "Hearing Loss Study at USC, Harvard Shows Hope for Millions" on the USC News website. The authors of the April 4, 2018, Bioconjugate Chemistry study, “Bisphosphonate-Linked TrkB Agonist: Cochlea-Targeted Delivery of a Neurotrophic Agent as a Strategy for the Treatment of Hearing Loss,” include lead researcher Judith S. Kempfle, as well as Christine Hamadani, Nicholas Koen, Albert S. Edge, and David H. Jung of Harvard Medical School and The Eaton-Peabody Laboratories/Massachusetts Eye and Ear in Boston. Kempfle is also affiliated with the University of Tübingen Medical Center. Corresponding author Charles E. McKenna, as well as Kim Nguyen and Boris A. Kashemirov, are at USC Dornsife.

The research was supported by the American Academy of Otolaryngology–Head and Neck Surgery Herbert Silverstein Otology and Neurotology Research Award, an American Otological Society Research Grant, and a grant from the National Institute of Deafness and other Communicative Disorders (R01 DC007174).

A Clinical Trial for a New Drug to Protect Hearing

By Yishane Lee

The U.S. Food and Drug Administration (FDA) has approved a novel drug to protect against ototoxicity (harmfulness to hearing) due to the use of aminoglycoside antibiotics to treat severe infections. The FDA approval paves the way for a Phase I clinical trial to test whether the drug, found to be significantly protective in animals, is safe for humans.

Mature lateral line hair cells from larval zebrafish (shown with the neuromast sensory organ enlarged) serve as a platform for studying drugs and genes that modulate hair cell susceptibility to ototoxic agents.

The drug, ORC-13661, was developed by University of Washington professors Edwin Rubel, Ph.D., and David Raible, Ph.D., who are members of Hearing Health Foundation’s Scientific Advisory Board and Hearing Restoration Project, respectively, and Fred Hutchinson Cancer Research Center scientist Julian Simons, Ph.D. “While this program was not directly funded by HHF, both David and I have definitely been supported by HHF for a long time,” Rubel says. “This is a drug to prevent hearing loss that we've developed over the past 15-plus years.”

Rubel points out the drug’s two main features: “It is a brand new drug with a composition of matter patent, not one that is used for other medical purposes and being repurposed; and it is the first drug that was developed, from the get-go, to protect hair cells from ototoxic injury.”

After screening libraries of potential chemicals to see which stopped hair cell death in zebrafish lateral line system, Rubel, Raible, and team identified the best candidate and then boosted its effectiveness by tweaking its chemical structure; results were published in the Journal of Medicinal Chemistry in January 2018.

Rubel adds, “Toxicity studies in zebrafish, rats, and dogs required by the FDA show superior safety and nearly 100 percent hearing protection at all frequencies.” If the Phase I trial shows the drug is safe for humans, the next step is to test its efficacy among patients using aminoglycosides.

New Data-Driven Analysis Procedure for Diagnostic Hearing Test

By Carol Stoll

Credit: Susan Prater, Flickr

Stimulus frequency otoacoustic emissions (SFOAEs) are sounds generated by the inner ear in response to a pure-tone stimulus. Hearing tests that measure SFOAEs are noninvasive and effective for those who are unable to participate, such as infants and young children. They also give valuable insight into cochlear function and can be used to diagnose specific types and causes of hearing loss. Though interpreting SFOAEs is simpler than other types of emissions, it is difficult to extract the SFOAEs from the same-frequency stimulus and from background noise caused by patient movement and microphone slippage in the ear canal.

2014 Emerging Research Grants (ERG) recipient Srikanta Mishra, Ph.D., and colleagues have addressed SFOAE analysis issues by developing an efficient data-driven analysis procedure. Their new method considers and rejects irrelevant background noise such as breathing, yawning, and subtle movements of the subject and/or microphone cable. The researchers used their new analysis procedure to characterize the standard features of SFOAEs in typical-hearing young adults and published their results in Hearing Research.

Mishra and team chose 50 typical-hearing young adults to participate in their study. Instead of using a discrete-tone procedure that measures SFOAEs one frequency at a time, they used a more efficient method: a single sweep-tone stimulus that seamlessly changes frequencies from 500 to 4,000 Hz, and vice versa, over 16 and 24 seconds. The sweep tones were interspersed with suppressor tones that reduce the response to the previous tone. The tester manually paused and restarted the sweep recording when they detected background noises from the subject’s movements.

The SFOAEs generated were analyzed using a mathematical model called a least square fit (LSF) and a series of algorithms based on statistical analysis of the data. This model objectively minimized the potential error from extraneous noises. Conventional SFOAE features such as level, noise floor, and signal-to-noise ratio (SNR) were described for the typical-hearing subjects.

Overall, the results of this study demonstrate the effectiveness of the automated noise rejection procedure of sweep-tone–evoked SFOAEs in adults. The features of SFOAEs characterized in this study from a large group of typical-hearing young adults should be useful for developing tests for cochlear function that can be useful in the clinic and laboratory.

Srikanta Mishra, Ph.D, was a 2014 Emerging Research Grants scientist and a General Grand Chapter Royal Arch Masons International award recipient. For more, see “Sweep-tone evoked stimulus frequency otoacoustic emissions in humans: Development of a noise-rejection algorithm and normative features” in Hearing Research.

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

Moving Toward a Future Free of Drug-Induced Hearing Loss

By Erik Robinson

A new special publication orchestrated by five of the nation’s leading hearing experts compiles the latest research into hearing loss caused by drugs and solvents—how it occurs, how to treat it, and how to prevent it.

HHF Council of Scientific Trustees member Peter Steyger, Ph.D., and colleagues produced a special Frontiers in Cellular Neuroscience publication on the topic of ototoxicity.

The compilation was published online as a special research topic by the journal Frontiers in Cellular Neuroscience on March 5, 2018. It includes both original research and focused reviews. The Pharmaceutical Interventions for Hearing Loss Working Group organized the effort at the behest of the Department of Defense (DoD) Hearing Center of Excellence.

“We’re trying to elevate ways for the human population to avoid losing this important sensation for experiencing and communicating with the world around us,” says coauthor Peter Steyger, Ph.D., a professor of otolaryngology/head and neck surgery in the Oregon Health & Science University (OHSU) School of Medicine, and a member of Hearing Health Foundation’s Council of Scientific Trustees.

“Ototoxicity is a threat to hearing at any age and hearing loss remains a significant side effect of chemotherapy. This review highlights how far we’ve come in understanding that threat and provides us with a roadmap for developing more effective ways to recognize and address the problem,” adds coauthor Jian Zuo, Ph.D., of the department of developmental neurobiology at St. Jude Children’s Research Hospital in Memphis, Tennessee.

In people, hearing cells don’t regenerate so the loss is irreversible. That’s why it is crucial to understand the mechanisms that affect hearing and how to prevent loss of hearing, Steyger says. The introductory editorial, “Moving Toward a Future Free of Ototoxicity,” highlights the latest scientific research exploring how certain pharmaceuticals damage the inner ear while others can protect it. It also highlights the need for better monitoring and detection of hearing loss over time, especially among patients being treated with antibiotics.

Steyger, who lost hearing as a child after being treated with antibiotics for meningitis when 14 months old, noted that hearing loss affects a surprisingly large proportion of the population—rising from an estimated 1 in 500 newborns to as many as half of all people age 75 or older. The research encapsulated in the new e-book includes 23 scientific articles from 93 authors and represents the state of the science in both prevention and treatment of ototoxicity hearing loss. (The e-book is available to all, free of charge.)

“This compilation will help to propel our knowledge forward and underscore the need to better understand the dangers of ototoxicity. The DoD Hearing Center of Excellence is honored to host and mobilize this important effort,” says coauthor Carlos Esquivel, M.D., a neurotologist and chief medical officer in the Clinical Care, Rehabilitation, and Restoration Branch of the DoD Hearing Center of Excellence at Joint Base San Antonio in Texas.

In addition to Steyger, Zuo, and Esquivel, the publication’s editors include Lisa Cunningham, Ph.D., of the National Institute on Deafness and Other Communication Disorders, and Kelly Watts, Au.D., of the DoD Hearing Center of Excellence.

This originally appeared in OHSU News and was republished with permission. 

Ménière's Disease Grantee Featured in Reader's Digest

Credit: Agnieszka Marcinska, Shutterstock

Ian Swinburne, Ph.D., a 2018 Ménière's Disease Grant (MDG) recipient, shared his expertise regarding vertigo with Reader's Digest in an article called "What Causes Vertigo? 15 Things Neurologists Wish You Knew" published in March 2018. 

"The spinning, dizzying loss of balance which earmarks vertigo can come without warning," the article opens. Various professionals provide information about its duration, how it feels, and different types.

HHF-funded Dr. Swinburne notes specifically that the inner ear and balance disorder Ménière's disease can cause vertigo. He explains that "[b]outs of vertigo likely arise in patients with Ménière's disease, because the inner ear's tissue tears from too much fluid pressure—causing the ear's internal environment to become abnormal.'" He is currently pursuing a research project to understand the inner ear stabilizes fluid composition, which he believes will help to identify ways to restore or elevate this function to mitigate or cure Ménière's disease.

View the full article from Reader's Digest, here.

Improving Diagnostic Test for Ménière’s Disease

By Wafaa Kaf, Ph.D., and Carol Stoll

Electrocochleography (ECochG) is a commonly used assessment of the auditory system, specifically the inner ear and the hearing nerve. ECochG is most often elicited by a brief acoustic stimulus, known as a “click,” at a relatively low repetition rate. It measures two key responses: summating potential (SP) and action potential (AP), which assist in the diagnosis of Ménière’s disease, an inner ear and balance disorder. Previous research has established that individuals with Ménière’s disease are likely to have abnormally large SPs and a large SP/AP ratio. Though click ECochG has great potential to detect Ménière’s disease, it lacks sensitivity, or the ability to correctly identify those with the disease. Only 69% of those with Ménière’s disease are correctly diagnosed, while 31% of those with the disease have normal ECochG results. This lack of accuracy prevents its use as a definitive diagnostic tool. Hearing Health Foundation 2015 Emerging Research Grants recipient, Wafaa Kaf, Ph.D., is researching the use of a novel analysis technique called Continuous Loop Averaging Deconvolution (CLAD) to best improve the sensitivity of ECochG to high click rate for diagnosing Ménière’s disease. Findings were recently published in Ear and Hearing 2017.

In a recently published paper in Frontiers in Neuroscience, Kaf’s research team shares its findings on the effects of altering the parameters of the acoustic stimulus on ECochG responses to quantify the effect of stimulus rate and duration of the elicited stimuli. Kaf and her research team obtained SP measurements to 500Hz and 2000Hz tone bursts that varied in duration and repetition rate from 20 adult females with normal hearing. CCLAD was used to interpret the tracings elicited by the differing stimuli of tone bursts.

They found that SP amplitude was significantly larger when using the highest stimulus repetition rate. It is believed that the high stimulus repetition rates minimize the neural contributions and mostly reflect hair cell responses, the target of ECochG. In addition, longer duration stimuli is believed to better reflect hair cell involvement while shorter stimuli may be useful in eliciting responses reflective of neural contributions. Lastly, 2000Hz tone bursts produced larger SP amplitude as compared to 500Hz tone bursts. Therefore, 2000Hz tone bursts with a high repetition rate and long duration can be used as parameters to minimize neural contributions to SP measures whereas short duration stimuli can be used if one wishes to asses neural activity.  

The data that Kaf’s team published is a critical initial advancement towards ultimately understanding the SP measurement in diseased ears. Their findings not only provide normative data for tone burst ECochG across stimulus frequencies, stimulus rates, and stimulus durations, but also help others better understand how to improve sensitivity of ECochG for early diagnosis of Ménière’s disease.  

Wafaa Kaf, Ph.D., is a 2015 Emerging Research Grants recipient. Her grant was generously funded by The Estate of Howard F. Schum.

WE NEED YOUR HELP IN FUNDING THE EXCITING WORK OF HEARING AND BALANCE SCIENTISTS. DONATE TODAY TO HEARING HEALTH FOUNDATION AND SUPPORT GROUNDBREAKING RESEARCH: HHF.ORG/DONATE.

Mapping Better Hearing

By Vicky Chan

Hearing Health Foundation (HHF) is grateful to the many individuals and organizations who have empowered groundbreaking hearing loss research in the last 60 years. A new interactive map displays every institution in the U.S. where HHF has been fortunate to fund groundbreaking research, yielding outstanding advancements in hearing and balance science. The map also indicates the rates of hearing loss in each state, signaling that additional work is urgently needed.

The colors—light yellow, yellow, green, teal, blue, and purple—represent the rates of hearing loss in each state. The calculations are based off 2015 U.S. Census Data, using estimates from the well-known prevalence of hearing loss among specific demographics. At the lowest end of the range in light yellow, hearing loss affects 13.71% of Colorado’s population. The highest rate was found in Missouri, purple, where the prevalence measured 20.15%. The mean for all states was 18.16%. The numbers signal the significance of hearing loss research.

Nearly all of the institutions on the map represent recipients of the Emerging Research Grants (ERG) who have carried out investigations related to tinnitus, hyperacusis, Ménière's disease, Usher syndrome, hearing loss in children, Central Auditory Processing Disorder, and strial atrophy.

A few institutions are home to the work of the Hearing Restoration Project’s (HRP) domestic consortium members, who focus on investigating hair cell regeneration as a cure for hearing loss and tinnitus. They conduct research at Baylor College of Medicine, Harvard Medical School, Oregon Health & Science University, Stanford University, Stowers Institute, University of Maryland, University of Michigan, University of Southern California, University of Washington, and Washington University.

By mid-year, the institutions corresponding to HHF’s newly formed Ménière's Disease Grants (MDG) program will be added to the map.

HHF envisions a world in which no one lives with hearing loss and tinnitus—until this is realized, we’ll do everything we can to put more innovative hearing loss research on the map.

Research Aims to Improve Fit and Increase Use of Hearing Aids in U.S.

By University of Maryland Department of Hearing and Speech Sciences

Photo Credit: Shutterstock

Although about 28.8 million Americans could benefit from wearing hearing aids, less than a third of that population actually uses them, according to the National Institutes of Health. While cost is a contributing factor, experts say many people with hearing loss choose not to wear hearing aids simply because they have difficulty adjusting to them. Researchers with the University of Maryland Department of Hearing and Speech Sciences (HESP) are hoping to improve those figures by developing better procedures for fitting people with hearing aids for the first time.

“Right now when someone is fitted with hearing aids, the focus is on increasing audibility of sounds reaching the ear,” says HESP Assistant Professor Samira Anderson, Au.D., Ph.D. “However, in order to actually understand what someone is saying, sound has to travel from the ear up to the brain. We’re interested in understanding how wearing a hearing aid affects that process.”

Dr. Anderson, University of Maryland Department of Hearing and Speech Sciences

In a study published recently in Ear & Hearing, Anderson and colleagues outfitted 37 older adults with mild to severe hearing loss with new, in-the-ear hearing aids donated by Widex USA. The researchers placed electrodes on the surface of the patients’ skin to measure electrical activity produced in response to sound in the auditory cortex and midbrain. They found that the brain’s processing of sounds improved while wearing hearing aids.

“There’s a growing body of research showing that hearing loss can lead to accelerated cognitive decline and isolation as people age,” Anderson says. “My hope is that we can develop enhanced testing procedures that will allow more people to benefit from hearing aids and enjoy a better quality of life.”

The UMD research team plans to continue evaluating the patients in their study during the first six months of hearing aid use. In future studies, researchers hope to investigate the effects of manipulating hearing aid parameters on neural processing. The study was funded by the UMD Department of Hearing and Speech Sciences, Hearing Health Foundation, and the National Institutes of Health (NIDCD Grant T32DC000046).

Samira Anderson, Au.D., Ph.D., is a 2014 Emerging Research Grants researcher generously funded by the General Grand Chapter Royal Arch Masons International. We thank the Royal Arch Masons for their ongoing support of research in the area of central auditory processing disorder. Read more about Anderson and her research in “A Closer Look,” in the Winter 2014 issue of Hearing Health.

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