Gene Therapy for Sensorineural Hearing Loss

Sensorineural hearing loss is an impairment that affects more than 360 million people worldwide. Recent studies suggest that 1.1 billion people could develop the disease during their lives.¹ Despite its widespread effects, the medical disability currently has no cure. However, gene therapy is an emerging treatment, designed to tackle the root causes of this morbidity.
Humans interpret sound primarily through the auditory hair cells, located in a portion of the inner ear known as the cochlea. Auditory hair cells are not actually hair cells but have been labelled as such because they sport microscopic hair-like projections known as stereocilia at the top of each cell.² When sound waves reach the inner ear, the stereocilia sway back and forth, opening up pore-like channels at the tips of the projections. As a result, sound waves are converted to electrical waves and electrical impulses are then passed through the auditory nerve and transmitted to the brain.³ Thus, if hair cells are damaged or missing, the connection between sound waves and the brain’s auditory processing center is broken, making it impossible to hear.
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Fig. 1: A visual depiction of healthy auditory hair cells located deep inside the inner ear.
Prolonged exposure to high intensity noise, genetic mutations, and ageing are the predominant ways that people damage their hair cells. Listening to sounds above 85 decibels for an extended period of time overstimulates the hair cells which begin to either bend, break, or completely shear off. Something as mundane as heavy city traffic reaches 85 decibels, while the sound of exploding firecrackers can reach 150 decibels. The greater the amplitude, the less time it takes for the auditory hair cells to become damaged.³ Even though external conditions do have a significant impact on hearing loss, the majority of people have attained the impairment from genetic conditions.
There are many different genetic mutations that prevent the body from producing fully-functioning hair cells. The most common genetic disorder is Usher’s syndrome. Usher’s syndrome involves irregular development and maintenance of the hair cells, and creates miscommunication in the transmission of sound waves.⁴ Similarly, people also lose their hearing when they grow older, as their healthy hair cells naturally begin to die off. Since hair cells control perception of sound, it is imperative to sustain them for as long as possible.
ATOH1 Gene Therapy- a solution to ‘common hearing loss’
Auditory hair cells are developed during prenatal stages, facilitated by Atonal Homologue 1, a protein encoded by the ‘ATOH1’ gene. The protein acts as a transcription factor that plays a critical role in hair cell differentiation and maturation. In mammals, the gene is silenced during the first week after birth. So, unlike other animals, when mammals damage their auditory hair cells, the resulting hearing loss is permanent.⁵ Gene therapy addresses this issue by reintroducing the ATOH1 gene to the cochlea to restart the development of hair cell growth. The process begins by isolating the ATOH1 gene from a bacteria and splicing it into an adenovirus, creating an adenoviral vector. Next, the gene-carrying virus is injected into the inner ear through a small incision in the eardrum and an even smaller laser-drilled hole in the bone that rests against the inner ear.⁶ The insertion forces the supporting cells in the cochlea to ectopically express the non-silenced ATOH1 gene.
Even though experimentation with ATOH1 gene therapy is in its infancy, results have been promising. In a recent study, guinea pigs were deafened by ototoxic drugs (to mimic age-related hearing loss), causing a complete destruction of hair cells after just three days. Afterwards, the cochlea were injected with the adenoviral vectors containing the ATOH1 gene. The outcome showed partial, but stable, hearing recovery, shown by the presence of hair cells exhibiting stereociliary bundles. The results confirmed that the ATOH1 gene had caused transdifferentiation in the supporting cells, validating the practicality of ATOH1 gene therapy. However, the experiment was limited by its inability to determine whether the observed hair cells were regenerated or whether they had simply been restored or repaired, providing only a temporary fix.⁷ Similar studies in which hearing loss was induced by noise rather than through the use of drugs have yielded comparable outcomes. Guinea pigs that were exposed to repeated, simulated gunfire and injected with the ATOH1 gene showed signs of stereocilia bundle restoration and higher rates of survival for damaged hair cells. In fact, approximately 58% of the guinea pigs’ hearing capabilities were recovered.⁸ With such assuring data, scientists have also conducted research with other genes.
USH1C Gene Therapy- a solution to Usher’s Syndrome
While ATOH1 gene therapy is excellent for the regeneration of hair cells, it does not fix the problem of improperly functioning hair cells. Hence, people with conditions such as Usher’s syndrome would have no benefit from this treatment. Usher’s syndrome primarily causes mutations in the ‘USH1C’ gene, which encodes the protein harmonin. Harmonin controls mechanotransduction in the auditory hair cells and is also critical for sustainment.⁴ Unfortunately, with Usher’s syndrome, the gene for harmonin is either incorrectly expressed, or ceases to even be produced depending on the severity of each individual\’s situation.
By utilizing a similar approach as ATOH1 gene therapy, but using the USH1C gene instead, research has already commenced, with the aim of providing a permanent treatment for Usher’s syndrome. In 2015, Harvard Medical School and Boston Children’s Hospital looked at mice with a mutation in the USH1C gene (they contained the exact same mutation of the USH1C gene as people with Usher’s syndrome). The mice were injected with a corrected version of the gene to observe the effects, if any, on hearing capability. After the corrected gene was introduced, hair cells in the cochlea began to produce normal, full-length harmonin. Since the mice were treated immediately after birth, they were able to produce healthy, functional hair cells.⁹ Click to enlarge
Fig 2: The leftmost picture above shows a control group of mice with no mutations and healthy hair cells in the cochlea. The middle column shows the bundles severely disturbed as a result of the mutation caused by Usher\’s syndrome. The rightmost column depicts the vast regrowth of the stereociliary bundles after gene therapy.
Although the experiment generated exceptional results, one constraint noticed was that when the procedure was done on mice eleven days after birth instead of immediately after, there were no positive effects on the mice’s harmonin.⁹ A possible reason for the disparity in success in mice of different ages is that after 11 days, all the cells in a mouse carry a mutated version of the USH1C gene but if a mouse is treated earlier in its life, a larger percentage of cells will eventually carry a replicated version of the replacement gene. Thus, if scientists were to apply the study to human treatments, the method would only work if the procedure was done right after birth. In fact, the age of an individual is one of the largest barriers to successful gene therapy. Replacing genes in the embryo of an organism is a much less extensive task then editing the genome of an adult, due to the vast increase in cells that have to be treated. A potential alternative could involve gene editing removed cells, culturing them to increase their numbers, and returning them to the ear.
Future Outlook
Though ample research has been done on animals, ATOH1 and USH1C gene therapy in humans is still in its developmental stage. ‘GenVec’, a clinical stage gene delivery company, has recently introduced project ‘CGF166’, which will deliver the ATOH1 gene to humans who have severe sensorineural hearing loss. While the delivery process is still being refined, CGF166 is said to be an available treatment for patients in late 2017.¹⁰ However, one thing patients might be wary about is the inconsistency with ATOH1 gene therapy, as procedures have slightly varying outcomes. Still, many may be enticed by the hope of finally curing their sensory impairment for good.
As for USH1C gene therapy, it could take some time before doctors start clinical trials on humans. The intricacies of harmonin have left scientists with many unanswered questions that must be addressed before the gene therapy is introduced to the public. One of the biggest questions that researchers have been unable to provide an explanation for is the vast change in results for USH1C gene therapy that was performed just days after birth as opposed to immediately after birth. Although patients can anticipate ATOH1 gene therapy before USH1C gene therapy, both treatments could make their public debuts in the coming years.
Yet, it is important to consider the shortcomings of gene therapy. The age of the individual (see above) is not the only issue facing genetic technology. Even when the corrected gene is re-inserted to the ear, researchers have speculated that the replacement gene can still become mutated. While there is no way to be sure that this will occur, the problem may defeat the entire purpose of gene therapy. Similarly, animal studies conducted on mice may not be as accurate as desired, since mice only share 96% similarity with the human genome. The seemingly negligible difference actually accounts for many of the discrepancies between testing on mice and clinical trials. For example, somatic cell nuclear transfer (another potential solution to sensorineural hearing loss) has so far been unsuccessful in human experimentation, yet the method was a breakthrough in the field of developmental biology when it was used to clone frogs for the first time . Since clinical trials have not started with ATOH1 or USH1C gene therapy, there is no way of telling if the positive results observed in the mice will be seen in humans as well.
Ultimately, as one of the more effective cures for sensorineural hearing loss, ATOH1 and USH1C gene therapy needs to be further developed to continue advancements in treatment so that the procedures can be implemented in human patients.
Key Terms

  • Cochlea: A sensory organ that resides deep within the ear and is filled with cochlear liquid. When the liquid vibrates, sound is converted to neural messages for the brain to interpret.
  • Stereocilia: Located in the cochlea, these are hair-like cells that move back and forth in the presence of sound and create electrical impulses to be transmitted to the brain.
  • Usher’s syndrome: A common condition that is harmful to hearing and vision. It is an autosomal recessive trait meaning that approximately 3 to 6 percent of all children who are deaf and another 3 to 6 percent of children who are hard-of-hearing have Usher syndrome.¹¹
  • Transcription factor: A protein that can increase gene transcription which allows for continuous protein production. It is also responsible for binding to nearby DNA to turn specific genes on or off.¹²
  • Adenovirus: Extremely stable, infectious agents with a large genome size that can replicate quickly in animals. Thus, they are very efficient to utilize in gene therapy. ¹³
  • Vector: An organism that acts like a “gene shuttle”, carrying the replacement genes into the cell.
  • Ectopically: Describes atypical gene expression in a cell which the gene would normally not be expressed.
  • Transdifferentiation: Refers to the conversion of one differentiated cell type to another.¹⁴ In ATOH1 gene therapy, supporting cells are converted to hair cells.
  • Mechanotransduction: The process in which cells sense and respond to stimuli (e.g. sound) by converting it to biochemical signals (i.e electrical waves to send to the brain).¹⁵
  • Somatic cell nuclear transfer: Refers to the process of reversing specialized cells back to their embryonic origin, before differentiating them down a certain line to form new inner ear cells.

¹ \”Deafness and Hearing Loss,\” World Health Organization, February 2017, accessed May 05, 2017,
² Rémy Pujol, \”Journey into the World of Hearing,\” The Cochlea, August 10, 2016, accessed May 05, 2017,
³ \”Noise-Induced Hearing Loss,\” National Institutes of Health, February 13, 2017, accessed May 05, 2017,
⁴ \”Harmonin,\” Universal Protein Resource, March 15, 2017, accessed May 05, 2017,
⁵ Cristy Lytal, \”USC Stem Cell Researchers Listen for Clues About How the Gene ATOH1 Enables Hearing,\” Keck School of Medicine of USC, July 5, 2016, accessed May 05, 2017,
⁶ \”Scientists Hope to Cure Hearing Loss With Gene Therapy,\” Electronic Shooters Protection, July 12, 2016, accessed May 05, 2017,
⁷ Rachel T Richardson, and Patrick James Atkinson, \”ATOH1 Gene Therapy in the Cochlea for Hair Cell Regeneration,\” Expert Opinion on Biological Therapy, March 2015, accessed May 05, 2017,
⁸ Wade W Chien, \”Gene Therapy for Sensorineural Hearing Loss,\” National Center for Biotechnology Information, accessed May 05, 2017,
⁹ \”Gene Therapy Restores Hearing in Deaf Mice, Down to a Whisper,\” ScienceDaily, February 6, 2017, accessed May 05, 2017,
¹⁰ Rena Cohen, \”FDA Lifts Clinical Hold On CGF166,\” GenVec, Inc, July 25, 2016, accessed May 05, 2017,
¹¹ \”Usher Syndrome.\” National Institute of Deafness and Other Communication Disorders. March 06, 2017. Accessed August 11, 2017.
¹² \”Transcription factors.\” Khan Academy. Accessed August 11, 2017.
¹³ \”Adenovirus.\” Nature News. Accessed August 11, 2017.
¹⁴ \”Transdifferentiation.\” Transdifferentiation. Accessed August 11, 2017.
¹⁵ \”Mechanotransduction.\” Nature News. Accessed August 11, 2017.
Photo by Dr. David P. Corey and property of the Theoretical and Computational Biophysics Group, NIH Center for Macromolecular Modeling and Bioinformatics, Beckman Institute, University of Illinois at Urbana-Champaign. See

4 thoughts on “Gene Therapy for Sensorineural Hearing Loss”

  1. Nancy Boyd

    I had sudden permanent hearing loss in one ear about 18 years ago. I was diagnosed by a specialist at Jefferson in Philadelphia as having a fistula form in my eardrum (from a cold) which permanently damaged the nerve in my ear. I live in Lancaster PA and would travel to find either a study or treatment by a specialist who can give me treatment options. I have no idea where to start. I live near Johns Hopkins and Philadelphia-based medical institutions. If you can guide me, even in the smallest way, I would be grateful. Thank you for the courtesy of your attention. Sincerely, Nancy Boyd

    1. John Hopkins is considered one of the best in the country of ENT medical issues. I would start there.

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