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Restoring Hearing Through Cell Reprogramming and Regeneration

Harvard scientists have developed a new hearing loss treatment that restores hearing via cell reprogramming and regeneration.

Researchers at Harvard Medical School are one step closer to restoring sensorineural hearing loss through cell reprogramming and regeneration. If successful, this biotechnology would address a centuries-old medical challenge, impacting millions globally.

Researchers made a revolutionary breakthrough in hearing loss treatment through new studies on mouse models. The research, published in the Proceedings of the National Academy of Sciences (PNAS), was led by Zheng-Yi Chen, PhD, Associate Professor of Otolaryngology-Head and Neck Surgery at Harvard Medical School.

“As we know, hearing loss is one of the most common forms of sensory deficit affecting humans,” Chen told LifeSciencesIntelligence.

According to the National Institute of Deafness and Other Communication Disorders (NIDCD), a subset of the National Institutes of Health (NIH), hearing is a complex and multistep process, meaning hearing loss can have multiple causes.

The hearing process starts with sound waves entering the outer ear through the ear canal, which vibrates the eardrum. These vibrations are then sent to the middle ear bones: the malleus, the incus, and the stapes.

The middle ear’s main functionality is to amplify the sound vibrations and send them to the cochlea in the inner ear. An article published in Neuroscience notes that there are two types of cochlear hair cells: outer hair cells and inner hair cells. The paper clarifies, “The inner hair cells are the actual sensory receptors, and 95% of the fibers of the auditory nerve that project to the brain arise from this subpopulation. The terminations on the outer hair cells are almost all from efferent axons that arise from cells in the brain.”

Hair cell loss is a critical factor contributing to hearing loss.

Hearing Loss Overview

In children, 2–3 of every 1,000 newborns are born with hearing loss, with 90% of deaf children being born to parents who can hear. Across adult populations, 15% of individuals have some trouble hearing.

The WHO estimates that 430 million people worldwide have advanced hearing loss that requires rehabilitation, accounting for 5% of the global population.

Johns Hopkins Medicine identifies three hearing loss categories, sensorineural hearing loss, conductive hearing loss, and mixed hearing loss. Chen adds that there are multiple pathologies or types of hearing loss, each requiring a unique approach to treatment.

Sensorineural Hearing Loss

Sensorineural hearing loss is caused by inner ear or hearing nerve damage. Commonly, sensorineural hearing loss is triggered by damage to hair cells in the cochlea, often caused by aging, loud noise exposure, injury, disease, drug use, or genetic conditions.

The National Council on Aging (NCOA) notes that age-related hearing loss, also called presbycusis, can be gradual and may go unnoticed initially; however, the NIDCD notes that aging is the most significant indicator of hearing loss.

“For genetic hearing loss, patients need gene therapy or genome editing,” said Chen. Meanwhile, noise-induced or age-related hearing loss may require drug therapy, including regenerative medicine. With these differences in mind, Chen and the rest of his lab have looked at varying modalities of hearing restoration.

To date, there is no cure for sensorineural hearing loss; however, many patients can manage their hearing loss through hearing aids or another assistive technology.

The NCOA notes that there are multiple different kinds of hearing aids. Until recently, the most common and accessible hearing aids were prescription. However, recent FDA approvals have allowed over-the-counter sales of hearing aids, which has widened access further.

Most hearing aids are bone-conduction hearing aids that amplify the vibrations, stimulating the inner ear.

Aside from hearing aids, for some patients, cochlear implants, a surgically implanted device that sends signals directly to the brain, may also be beneficial.

Conductive Hearing Loss

Conductive hearing loss is caused by a blockage in the outer or middle ear that prevents sound waves from reaching the inner hair cells. These blockages may include earwax, foreign objects, impacted fluid in the middle ear, infection, skeletal abnormalities, or eardrum injury. Some cases of conductive hearing loss can be treated through a procedure to remove the blockage, such as ear wax or foreign object removal.

Mixed hearing loss is a combination of the two forms.

Chemotherapy Associated Hearing Loss

“Hearing loss can be caused by chemotherapy, including cisplatin,” noted Chen. “Patients could also be exposed to other drugs, like antibiotics, aminoglycoside type of antibiotics, kanamycin and gentamicin. In high doses, they all will damage ear air cells.”

There are two strategies to manage hearing loss linked to chemotherapy and other cancer treatments. The first strategy is not necessarily a management tool but involves preventing drug-induced hearing loss.

“There is an FDA-approved drug ready to prevent cisplatin-induced hearing loss,” revealed Chen.

Regarding antibiotics, providers and clinicians can do their best to avoid high-dose antibiotics that may impact the inner ear; however, under certain circumstances, there is no way to prevent the drug’s use or impact effectively.

“For all the people who already have this hearing loss, the better treatment option will be through the regeneration of sensory hair cells,” offered Chen. “We know cisplatin, or the aminoglycoside antibiotics, all damage your hair cells preferentially. Then it will lead to degeneration of other cell types. But hair cells are the primary target.”

Cell Reprogramming and Regeneration

“In the lab, we have been working on regeneration, which will target the largest population of patients with hearing loss, and then we also have a drug development,” he continued.

The study reveals that many other species, including birds and fish, have spontaneous hair cell regeneration; however, mammalian cochlea does not spontaneously regenerate these cells.

Hair cell regeneration research has been explored for over three decades; however, until recently, regeneration research focused on neonatal or embryonic animals’ inner ears. Although researchers hoped to look at adult animals, the approaches that worked very well in younger mice failed in older animals.

“Why do we need to regenerate hair cells in an adult?” mused Chen.

Research showed that adult animals had a fully matured inner ear. Animal models’ ears develop over time, while, in humans, a newborn baby is born with fully developed mammalian inner ears, comparable to the inner ear of an adult animal.

The mouse cochlea undergoes cell development throughout a mouse’s lifespan, while the human cochlea is fully developed at birth.

“Clinicians have to be able to show the treatment — whatever methodology they’re developing —  must be used to regenerate new hair cells in a fully mature adult mouse inner ear because the human inner ear is fully mature. So if they cannot achieve that, it likely won’t work in a human,” expanded Chen.

Reprogramming

“A few years back, researchers identified two genes, Myc and Notch1,” he continued. “We showed that if we use a genetic transgenic animal model, where we can use genetic means to turn on these two transcription factors, we can reprogram a fully mature adult mouse inner ear.”

Activating these two transcription factors helps supporting cell proliferation in animal models. These cells surround inner ear hair cells.

According to Chen, the researchers could make these supporting cells more responsive to hair cell induction signals by over-expressing Atoh1.

“Normally, they do not become a hair cell, but after reprogramming, they can respond to Atoh1, and then they become a hair cell.”

Throughout the conversation with LifeSciencesIntelligence, Chen discussed the idea of cell reprogramming.  

“Reprogramming turns the biological clock backward, so, even in the fully mature aged animal, we turn the Myc and Notch1 on and make them young again,” Chen noted.

While Notch1 can easily be activated through a chemical compound, valproic acid (VPA), activating Myc poses an additional challenge. Without a known molecule to turn on the gene, researchers identified two genes, Fir and Mxi1, that suppress Myc. Clinicians inactivated the suppressor genes, activating Myc in the process.

Regeneration

“Through our RNAseq study, we also identified some other pathways important in hair cell regeneration in the transgenic animal,” said Chen.

During the treatment, scientists gave the mature adult mice a cocktail of factors that address these pathways, creating wild-type mice with ears comparable to the human inner ear. After the cocktail treatment, the mice are given Atoh1 to regenerate hair cells.

To verify that the treatment could work in vivo, researchers gave wild-type mice Cynomycin to kill existing hair cells to induce deafness in the mice and test the efficacy of the regeneration model.

The cocktail is delivered using a needle inserted into the eardrum to deliver the mixture into the middle ear. The mixture then migrates into the inner ear. Afterward, Atoh1 is delivered using adenovirus through a surgical procedure in the inner ear.

Challenges

“In a current study, we couldn't restore hearing for several reasons. One is that we used adenovirus to target the supporting cells,” added Chen. No known adeno-associated viruses (AAV) can target supporting cells in the inner ear. As an alternative, researchers used an adenovirus.

“Adenovirus is very toxic to hearing, even in wild-type mice who can hear well; giving them adenovirus actually kills the hair cell. They don't hear again,” noted Chen.

Although the delivery method for Atoh1 has been shown to regenerate hair cells, it is not sufficient for long-term studies on hearing.

Beyond the toxicity of adenovirus, the delivery requires a surgical procedure that pierces through the bone, causing damage to the ear. Although an AAV procedure would be less invasive and mitigate damage to the inner ear, researchers have not found an appropriate AAV vector to perform gene therapy.

“Hearing loss is a significant issue affecting all of us, and treatment options are minimal. Traditionally, the field has lacked support because people had no treatment options,” reiterated Chen.

“I think we are really at a turning point where we'll see a new revolutionary novel treatment come on board from gene therapy to regeneration. This has the potential to transform not only our field of hearing loss but also could have an impact in other fields.”

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