Hearing Restoration Project

Moving Beyond Wnt and Notch Pathways for Hair Cell Regeneration

By Christopher Geissler, Ph.D.

There are several active human clinical trials evaluating the safety of inner ear hair cell regeneration therapies, but these therapies’ target mechanisms may be insufficient to stimulate hair cell growth in the adult mammalian cochlea. These approaches rely on the canonical Wnt and Notch signaling pathways and the Atoh1 molecule, which is necessary for hair cell regeneration and is regulated by these pathways. 

However, a report published in Molecular Therapy in May 2019 by Anshula Samarajeewa, Bonnie E. Jacques, Ph.D., and Alain Dabdoub, Ph.D., a member of Hearing Health Foundation (HHF)’s Hearing Restoration Project (HRP) consortium, notes that there has been very limited success thus far in regenerating hair cells in adult mammalian cochlea using these signaling pathways. This likely means, the authors write, that researchers will need combined approaches that also use epigenome-editing techniques to address changes to the genetic material and activity that occurs with age. 

Both the Wnt and Notch pathways play a role in determining how inner ear cells develop into specific types of cells and multiply, and they are also important in the development of the cochlea as a whole. Activating Wnt pathways and inhibiting Notch pathways can turn supporting cells into hair cells in fetuses and newborn mammals, making these key targets for hair cell regeneration. But both become much less effective as the body ages. Manipulating these pathways in adult animals has led to some success in regenerating hair cells, but these new hair cells tend not to develop fully, do not form necessary connections with auditory neurons, or even survive.  

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This lack of success is not because these pathways no longer exist in adults; researchers have found that they are still functional. This suggests that there are epigenetic changes that occur as a result of aging to make the adult cochlea less receptive to regeneration. Targeting epigenetic enzymes in addition to the Wnt and Notch signaling pathways may therefore prove more successful, but researchers still need to determine which part of the chromosome to target. This process would involve gene-editing techniques like CRISPR. This type of epigenome editing has slowed hearing loss in newborn mice, but it has yet to be tried in adult mice. If successful, this technique has the potential to treat hereditary and acquired forms of hearing loss.

HRP consortium member Alain Dabdoub, Ph.D., is a senior scientist, biological sciences at Sunnybrook Research Institute, University of Toronto. For more, see hhf.org/hrp.

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Operation Regrow Returns June 17

By Gina Russo

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Which came first—the chicken or the egg? It’s an age-old question, but luckily it does have a scientific answer: the egg.

At Hearing Health Foundation (HHF), researchers are working tirelessly to solve a different, unanswered scientific question: How do we cure human hearing loss?

Hearing is a vital sense and precious gift that so many, due to their genetics, noise exposure, ototoxic medication, age, or injury, have lost. Hearing loss impacts 50 million Americans and more than 460 million people worldwide.

At HHF, it’s not about the chicken or the egg. It’s about hearing. That’s what comes first in our lives and in our work. Hearing enables communication with loved ones and enjoyment of life.

Currently, the most common treatments available are hearing aids and cochlear implants. While miraculous in their impact, they do not recreate typical hearing. They do not undo the damage to the inner ear, or the cochlea, or regrow the sensory cells, or hair cells, which make hearing possible. This is why hair cell regeneration therapy is so urgently needed.

Hearing regeneration is already possible in frogs, fish, and yes, chickens. With your help, the members of HHF’s Hearing Restoration Project (HRP) can accelerate their studies to identify permanent cures and better the lives of millions.

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You can be part of the change. Make a donation to the second annual Operation Regrow campaign beginning Tuesday, June 17, at 9:00 AM EDT. Gifts will be accepted online and by mail until June 27.

Your generosity and commitment in this life-changing effort is invaluable to HHF and the scientists in the HRP. Thank you for inspiring us every day to work harder for you and your loved ones living with hearing loss.

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The Countdown to Operation Regrow

By Gina Russo

Hearing Health Foundation (HHF) is counting down the days until the start of Operation Regrow, a two-week movement when you can help us to further progress toward better treatments and cures for hearing loss.

Beginning Tuesday, June 5, at 8:00 AM EDT, you can support the team of scientists conducting life-changing research to restore lost hearing, and more importantly, your generosity will have double the impact! All contributions received by 11:59 PM EDT on Tuesday, June 19 will be matched by an anonymous donor.

Transverse section through the embryonic day 20 chicken utricle (inner ear organ) at 20X magnification. Photo by Amanda Janesick, Ph.D., of the lab of Stefan Heller, Ph.D., a Hearing Restoration Project consortium member

Transverse section through the embryonic day 20 chicken utricle (inner ear organ) at 20X magnification. Photo by Amanda Janesick, Ph.D., of the lab of Stefan Heller, Ph.D., a Hearing Restoration Project consortium member

With just five days remaining until launch, you can share the five most important facts about Operation Regrow with friends and family:

  1. The Hearing Restoration Project (HRP) is the HHF-funded scientific consortium dedicated to finding biological cures for hearing loss.

  2. Damage to the sensory cells in the human inner ear causes irreversible hearing loss.

  3. The HRP members know that the key to hearing loss cures is the human ability to regrow cells in the inner ear. This phenomenon is already possible in certain species. The HRP has observed cell regrowth in chickens, fish, and young mice.

  4. The HRP is comprised of 15 senior scientists who work collaboratively by openly sharing data and ideas, and this collaboration helps to speed up the research process.

  5. HHF maintains stellar charity ratings from Better Business Bureau Wise Giving Alliance, Guidestar, Charity Navigator, and CharityWatch for using 100% of donations to support critical research, ensuring that all Operation Regrow contributions will directly help the HRP.

If you are able to make a gift to Operation Regrow, please visit www.hhf.org/regrow between June 5 and June 19. Gifts may also be made by phone during business hours, 9:00 AM to 5:30 PM EDT, at 212-257-6140. We’ll be sure to keep you updated on our progress. Thank you for supporting HRP and hearing health!

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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

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).

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New Method Enables Systematic Study of Hair Cell Loss and Regeneration in Chickens

By Carol Stoll

Most forms of hearing loss are permanent because damage to inner ear sensory hair cells is irreversible in mammals, including humans. Mammalian vestibular hair cells have the potential to regenerate albeit at a low rate, but the hair cells of the adult mammalian cochlea are not regenerated. Birds, however, have a robust regenerative response to hair cell damage and are able to restore structure and function in inner ear organs. Consequently, the study of the molecular mechanisms that trigger the onset of avian hair cell regeneration in the balance organs as well as in the cochlea is important and may lead to therapies for hearing loss in humans.

This image shows the undamaged and damaged utricle, an inner ear balance organ, in a chicken. HRP researchers have devised a new method to study the precise timing of hair cell regeneration in chickens using a single surgical application of an ototoxic drug. Photo by Amanda Janesick, Ph.D.

This image shows the undamaged and damaged utricle, an inner ear balance organ, in a chicken. HRP researchers have devised a new method to study the precise timing of hair cell regeneration in chickens using a single surgical application of an ototoxic drug. Photo by Amanda Janesick, Ph.D.

Past experiments that investigate these regeneration mechanisms in living chickens required multiple injections of a drug to induce hair cell loss, making it difficult to determine the exact timing of the regeneration response. A collaboration of two Hearing Restoration Project researchers, Stefan Heller, Ph.D. and Jennifer Stone, Ph.D., and two talented postdoctoral fellows from their laboratories was recently published in Journal of the Association for Research in Otolaryngology identifying a potential solution to this problem. They developed an experimental framework that uses a single ototoxic drug application, enabling them to study the precise onset and timing of hair cell regeneration in vivo.

Heller, Stone, and colleagues performed their experiments on a total of 75 chickens. At seven days of age, the chickens were anesthetized and underwent surgery to eliminate hair cells in the inner ear organs. During the surgery, streptomycin (an ototoxic antibiotic) was delivered to the chicken’s inner ear. At various time points after the surgery, two sensory organs—the utricle, a vestibular organ; and the basilar papilla, the hearing organ—were dissected, labeled for various cellular markers, and analyzed under a microscope. Hair cells and their surrounding supporting cells were counted and observed for damage. EdU, a marker of cell division, was administered to the chickens to determine whether or not new hair cells were generated by cell division. These techniques enabled the researchers to quantitatively characterize the regenerative response of the utricle after damage.

The results of the study demonstrate that surgical application of a single streptomycin dose is a feasible approach to elicit hair cell loss and regeneration in the chicken utricle and basilar papilla. Just hours after streptomycin delivery, hair cell numbers significantly declined and DNA replication was activated. The team was then able to record specific events of the regeneration process, which get initiated around 12 hours after streptomycin-induced hair cell loss, and continue over the course of several days.

Supporting cells produce new hair cells either by converting into a hair cell (direct transdifferentiation), or by dividing, usually asymmetrically, into a supporting cell and a hair cell.  Throughout this regenerative response, supporting cell numbers and density in the utricle remain relatively constant, suggesting that there is a mechanism that responds to specific levels of damage and coordinates the individual events of the regeneration process.

The study establishes a framework for the refined study of the two modes of hair cell regeneration in the chicken utricle. The next steps of the work will focus on understanding the exact timing and mechanism of coordination of the regeneration response. With only a single application of streptomycin necessary to induce near-complete hair cell loss in hearing and balance organs, the new animal model allows for study of the entire process including initiation, realization, and termination. The fundamental understanding of the avian regenerative mechanisms may lead to future development of therapies for loss of hearing and balance in humans.

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

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Therapies for Hearing Loss: What Is Being Tested?

By Pranav Parikh

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Untreated hearing loss is linked to a lower quality of life, physical functionality, and communicative ability. The most common type of hearing loss, sensorineural, is often a result of damage to the delicate sensory hair cells in the inner ear. Because hair cell loss is irreversible, and hearing impairment therefore permanent, new treatment strategies are a welcome sign. In the July 2017 issue of Otology & Neurotology, Hearing Restoration Project (HRP) consortium member Ronna Hertzano, M.D., Ph.D., and Debara L. Tucci, M.D., a member of Hearing Health Foundation’s Council of Scientific Trustees (CST), along with Matthew Gordon Crowson, M.D., examined the field of emerging therapies for sensorineural hearing loss.

The team identified 22 active clinical drug trials in the U.S., and reviewed six potential therapies. Four use mechanisms to reduce oxidative stress believed to be involved in the inner ear cell death. Three of the therapeutic molecules being tested—D-methionine, N-acetylcysteine (NAC), and glutathione peroxidase mimicry (ebselen)—act as antioxidants to mop up free radicals caused by noise or other trauma to the inner ear. (For more about D-methionine, see page 11.) The fourth, sodium thiosulfate, is a chemical found to counteract the ototoxic effects of chemotherapy drugs.

The fifth approach is to manipulate the “cell death cascade.” This occurs when cells endure significant stress or injury, leading to the release of free radicals and changes in pH and protein that then kill the cell. Since hair cells do not regenerate like other cells, the cell death cascade causes permanent hearing loss. A trial is underway to make the cochlear neuroepithelium (inner ear tissue) more resilient to cell death signaling, using an inhibitor called AM-111 to block the chain of events leading to cell death. Finally, the sixth approach is a novel hair cell replacement therapy using the gene Atoh1, known to be a vital regulator of hair cell regeneration, causing cells to differentiate (change) into hair cells. Using mouse models, it has been shown that if Atoh1 is blocked, hair cell differentiation does not occur, and if it is induced, hair cell formation occurs, at least in the ears of very young mice.

Drug delivery methods to the inner ear are also being investigated. In addition to orally, delivery methods include a topical ear gel, intravenous infusion, and, most revolutionarily, direct injection of viruses to deliver genes to the inner ear. And while many of the drugs had to overcome hurdles to reach late-phase clinical trials, questions about safety, efficacy, and side effects remain, in addition to whether animal model results translate to human biology.

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HRP consortium member Ronna Hertzano, M.D., Ph.D. (far left), is an assistant professor at the University of Maryland School of Medicine. HHF CST member Debara L. Tucci, M.D., is a professor at Duke University Medical Center in North Carolina.

This article originally appeared in the Fall 2017 issue of Hearing Health magazine. Find it here, along with many other innovative research updates. 

Empower the Hearing Restoration Project's life-changing research. If you are able, please make a contribution today.

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High-Tech Hope for the Hard of Hearing

"In 2011, the Hearing Health Foundation based in New York, created the Hearing Restoration Project, a consortium of fourteen scientists who agreed to work together toward that goal, partly with funding from the foundation. One of the originators of the project, Edwin Rubel, who was a co-discoverer of hair-cell regrowth in chickens, told me, “It’s potentially the best thing that ever happened, because it really does bring together a lot of different kinds of expertise.”

Hearing Health Foundation's work toward finding better therapies and cures for hearing loss and tinnitus was featured in the April 3, 2017 Issue of T High-Tech Hope for the Hard of Hearing he New Yorker Magazine. Read the article here.

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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.

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HHF Supporter Alex Mussomeli Selected as Finalist in 2016 Oticon Focus on People Awards

By Oticon

Alex Mussomeli  of Westport is among the outstanding individuals with hearing loss selected as a finalist in 2016 Oticon Focus on People Awards, a national competition that celebrates individuals who are helping to eliminate negative stereotypes of what it means to have a hearing loss.  The soon-to-be sixth grader is one of three outstanding young people selected as a finalist in the Student category.  Beginning June 20, people can cast their vote for Alex at www.oticon.com.  Total number of votes will help determine whether Alex is the first, second or third place winner in the national awards competition. 

This is the 18th year that the Oticon Focus on People Awards has honored hearing impaired students, adults and advocacy volunteers who have demonstrated through their accomplishments that hearing loss does not limit a person’s ability to make a positive difference in the world.



Alex, diagnosed with hearing loss as an infant, appreciates the advances in hearing research and technology that have made his life easier and happier. The gifted musician and artist is determined to use his talents so other children with hearing loss can experience the benefits he has enjoyed. He found his inspiration in a legally blind artist who raised $1 million for charities benefiting children through the sale of his paintings.  This April, Alex held his first solo art show to benefit the non-profit Hearing Health Foundation’s Hearing Restoration Project. The young artist worked diligently for a year on the colorful acrylic paintings, prints and notecards that raised a whopping $16,000 for the Foundation.

Website visitors are encouraged to read all of the stories from this year’s 12 finalists in four categories: Student, Adult, Advocacy and Practitioner. 

Voting closes on August 15. Winners will be announced in September.

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HHF's FY'15 Annual Report: Read It Now

By Morgan Leppla

Hearing Health Foundation (HHF) is pleased to announce that our 2015 annual report is now available. From the latest hearing research to how we have worked to fulfill our mission, the report is a comprehensive look at our programs, events, and activities for fiscal year 2015 (Oct 1, 2014 - Sept 30, 2015).

In the report, we review HHF’s progress, talk to supporters, and decode the financials. Here are some highlights:

  • Check out the incredible supporters who ran, hiked, and hosted events all to benefit HHF’s mission!

  • HHF’s Hearing Restoration Project (HRP) consortium of researchers made notable strides in hearing and tinnitus research. In 2015, the HRP designed a model to test candidate hair cells for regeneration in deafened adult mice, and that’s only a fraction of the story.

    • HRP researchers like Andy Groves, Ph.D., thank you. “Federal funding for biomedical research has decreased by over 20% since 2003, and it shows no sign of increasing any time soon. Your support is critical to help support the skilled young scientists in my lab and to keep the lab afloat,” he says.

  • HHF awarded ten Emerging Research Grants (ERGs) to innovative scientists in the areas of Central Auditory Processing Disorder (CAPD), Hyperacusis, Ménière’s Disease, and Tinnitus. Learn more about what they are doing with their research grants.

  • See if your name made the donor list. Didn’t see your name...make a gift by Sept 30, 2016, to be listed in fiscal year 2016’s annual report.

  • Keep your eye (or ear!) out for hearing-related facts and statistics.

Get all the details in the full report here. We are excited by our progress over the past year and hope you enjoy reading it. As always, have any questions, please email us at info@hhf.org!

Please consider making a gift today so we can continue to carry out our mission and find a cure for hearing loss and tinnitus.


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