Gene Therapy for Hearing Loss on the Horizon : The Hearing Journal

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Gene Therapy for Hearing Loss on the Horizon

Glantz, Gordon

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The Hearing Journal 75(1):p 14,15,16, January 2022. | DOI: 10.1097/01.HJ.0000812688.91831.57
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Turn up your hearing aid, will ya?

F1 Gene therapy, hearing loss.

As lewd and crude and rude as it sounds, it is the general response for the person on the street, even if muttered underneath his or her breath, when dealing with someone—friend, family, co-worker, etc.—who suffers from mild to moderate hearing loss.

Aside from some surgical procedures that are not as commonly known, hearing devices—while being constantly upgraded in the digital age—have been the traditional source of help.

But there is one other ray of hope burgeoning on the horizon: Gene therapy.

From the Ivy League to the University of Miami to the University of Michigan to Oregon State to Tel Aviv, experts are on the verge of cracking the case.

“Although not yet available, inner ear gene therapy for monogenic hearing loss is an emerging technology,” explained Jeffrey R. Holt, PhD, a professor of Otolaryngology & Neurology at Harvard Medical School and of Boston Children’s -Hospital. “There is growing interest from scientists, funding agencies, industry and patients, all spurred on by recent proof-of-concept studies showing recovery of auditory function in animal models of human hearing loss.”

Holt added that genetic treatments for hearing loss sit on the horizon and the significance of this new therapeutic strategy for patients and families is high.

Nonetheless, he cautioned that the most common forms of genetic hearing loss, the result of mutations in GJB2, may be difficult to treat using gene therapy. Other rare forms of genetic hearing loss, due to mutations in OTOF, TMC1, or Usher syndrome, may be those first in line, but others will like follow.

Fan-Gang Zeng, PhD, the director of the Center of Hearing Research at the University of California-Irvine School of Medicine, explained that gene therapy addresses hearing loss biologically by repairing or restoring damaged cells, which hearing aids or cochlear implants do not accomplish.

“Gene therapy is the future, but we don’t know when the future will come,” he said. “While gene therapy is still in infancy, genetic screening of hearing loss is relatively matured. Concurrent screening with traditional audiological measures (OAE and ABR) and genetic testing can improve both the accuracy and prognosis of hearing loss while helping patients and doctors predict its course of development and management on an individual basis.”

Yehoash Raphael, PhD, is a professor of Otolaryngology at the University of Michigan’s Kresge Research Institute. He has been recognized around the globe for his research, the interests of which include inner ear biology, protection and regeneration, gene therapy, genetic deafness, CHARGE Syndrome and stem cell therapy.

Raphael believes gene therapy should be advanced for several clinical conditions, both environmental and genetic.

“At the cellular level, the goals would be related to repair and regeneration of cells that are injured or lost,” he said. “At present, amplification or cochlear implants provide an acceptable solution for many patients.”

He cautioned, however, the biological therapy that restores function may work better, but is not currently available.

“Ideally, we would like gene therapy to improve so it can be used for treating genetic deafness and sensorineural hearing loss caused by hair cell loss due to overstimulation, aminoglycosides, or infections,” he said. “As such, gene therapy presents an exciting prospect for future hearing restoration therapies.”


At Michigan, Raphael and his colleagues are using combinatorial gene transfer methods to enhance the efficiency of new hair cells and are planning to enhance this approach and include other genes.

“We are working on two mouse models for genetic inner ear disease, trying to better understand the biology of the mutation and also to design therapies,” he said, adding that the research on therapies has met with mixed results.

Holt’s lab has focused on development of gene therapy for patients with mutations in TMC1 and for Usher syndrome patients.

“We have remarkable data showing full recovery auditory function in some cases,” he said. “We are working with industry partners to bring these therapies into the clinic.”


Meanwhile, in the private sector, companies such as Decibel Therapeutics are also seeking solutions.

According to Laurence Reid, PhD, it is simply a case of seeing the need and seeking to answer it.

“The impact of significant hearing loss and balance disorders on individuals is profound and disrupts their connectivity with their human and physical environment,” said Reid, the CEO of Decibel. “We believe the inner ear represents an exciting new frontier for gene therapy, which will result in a pipeline of transformative medicines.”

Reid added that the inner ear is an organ that is “exquisitely suited” to gene therapy. As such, the therapy can be delivered directly to the relevant cells, which are non-dividing and offer a durable potential for gene therapy. Lastly, the ear has a degree of immune privilege, which will moderate immune response against the therapy.

Said Reid, “We are developing technologies that enable precision gene therapy, which will enable us to control the expression of the transgene in the gene therapy and limit the resulting pharmacology to precise cell types in which we intend to elicit a biological response.

“Programs are in development to address both hearing loss and balance disorders and our therapies will comprise treatments for genetic forms of hearing loss, together with regenerative medicines, to treat acquired forms of hearing and balance disorders.”


Looking ahead at the future of gene therapy as related to hearing loss, Raphael explained that the current technology for gene transfer for inner ear therapy needs to be improved in several cardinal and critical aspects to become a clinical reality.

He added that some of the parameters that need to be optimized include high cell-specificity, control of duration and extent of gene expression (how long and how much), acceptable route for delivering the vectors into the target site, and lack of toxicity and other side effects.

“All these parameters are being addressed but still far from being accomplished,” he said. “Lack of accurate and reliable diagnostic tools, especially related to hair cell loss, also complicate the implementation of gene transfer technology.”

Better technology would include upgraded batteries of tests that can predict the condition of the auditory epithelium, auditory nerve and other structures that are needed for biological hearing.

“The promise of hearing restoration would become more realistic with these parameters resolved,” he said.

Holt also cautioned against expected results tomorrow or the next day.

“While hopes are high that this may soon be a therapeutic option for some patients with genetic hearing loss, it is important to keep in mind that a careful and systematic approach will be required to fully understand both the safety and efficacy of this treatment modality,” he said. “There are at least 100 forms of genetic hearing loss and each will need to be evaluated before use in patients can commence.”

Reid further explained the importance of expanding access to genetic testing so families can understand the roots of their child’s congenital hearing loss and seek out relevant clinical trials and ultimately tailored therapies.

Noting that accurate diagnosis of infant hearing loss is crucial to developing new treatments and providing clinical care, Reid added that Decibel has–in collaboration with Invitae–launched Amplify, a sponsored testing program in the U.S. and Australia.

“This program provides genetic testing at no charge for children with auditory neuropathy and aims to drive awareness of genetic testing and gain physician interest, as well as support enrollment into future clinical trials,” he said.


What does all this mean for audiology professionals?

Holt predicts that audiologists will be an important part of the hearing health care team as this new wave of therapeutic options enters clinical trials, eventually wins approval, and becomes more broadly available.

He added that evaluation of auditory function before and after gene therapy treatments will be critical for understanding the efficacy, durability, and therapeutic window for hearing preservation and restoration.

“In preparation for the coming wave, audiologists can understand basic genetics, familiarize themselves with the various genes associated with genetic hearing loss, and be prepared to field patient questions,” he said. “I suspect that as soon as the first inner ear gene therapies enter clinical trials, there will be an explosion of patient interest and inquiries. However, inner ear gene therapies will not be a magic bullet cure-all. Rather, a precision medicine approach will be required, as these therapies will need to be tailored to each patient’s specific genetic diagnosis.”

Zeng had a similar view and explained that future audiologists will need to learn and understand the genetic component of hearing loss, which contributes half or more to the prevalence of hearing loss.

“Don’t expect gene therapy to be a silver bullet that can solve all the problems,” said Zeng. “There are a lot of things that gene therapy cannot solve (i.e., hearing loss related to mental issues).”

Raphael made the distinction between audiologists doing research and clinicians, advising those in research to consider joining the research efforts to design diagnostic means that will determine presence/absence of hair cells and/or neurons, and if hair cells are absent, where in the cochlea this condition exists and what state the supporting cells are in.

He added: “Are they differentiated or flat? The condition of supporting cells is an important factor in planning the set of genes that will be used to generate new hair cells.”

Raphael explained that audiologists in the clinics need to be aware that there are currently no therapies based on gene transfer being offered. “In some cases of genetic hearing loss, when the diagnosis is clear and the gene involved is not a very large gene, there is a chance that gene therapy could be offered in the relatively near future.”

He added that this is especially true for mutations that affect hair cell, and where the hair cells survive but do not function properly.

“I have a feeling that many of the patients asking about gene therapy options are those experiencing age-related hearing loss, which most of us are likely to develop at different speeds of progression,” he said. “Because many of these cases have long-term loss of hair cells and likely at least some neuronal regression or degeneration, the application of gene therapy would be very complex and challenging.”

Reid added that, over the next several years, Decibel hopes that a range of pharmaceutical interventions will become available to people with hearing loss and their caregivers.

“Audiologists will thus have therapeutic options in addition to the existing devices, which assist hearing improvement,” he said. “Diagnosis of particular forms of hearing loss will expand to include broader consideration of genetic mutations responsible for hearing loss.”

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