Gene Therapy to Counteract Human Deafness Draws Closer : The Hearing Journal

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Gene Therapy to Counteract Human Deafness Draws Closer

Laberta, Valerie

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The Hearing Journal 69(7):p 22,23,26, July 2016. | DOI: 10.1097/01.HJ.0000489188.31562.7e
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Illustration Source/Roy Scott

While genetic medicine has already wrapped its arms around most sectors of health care, its practical application in preventing hearing loss remains on the horizon. However, recent research sees the horizon line drawing closer, thanks, in part, to some jumping mice.

Richard Smith, MD

“The diagnosis of genetic hearing loss used to be an exclusionary diagnosis,” said Richard Smith, MD, director of the Molecular Otolaryngology & Renal Research Laboratories (MORL) at the University of Iowa. “But now, with comprehensive genetic testing and complementary bioinformatics after an audiogram, the next best test for anyone who is hearing impaired is comprehensive genetic testing.”


Before looking at the promise of those lurching rodents, it is important to understand the impact that molecular medicine is having on clinical practice today.

The importance of current molecular testing has less to do with the existence of hearing loss than with the type of hearing loss—and for patients, that information can be monumental. “One of the more common causes of recessive hearing loss is a complex variation of a gene called stereocilin (STRC) and a neighboring gene called CATSPER2. When both of these genes are deleted, the result is mild-to-moderate hearing loss,” explained Smith. “But if you're male, you also have infertility. That's not something that would be immediately recognized.”

Another example is the Usher syndrome, which is a genetic condition characterized by hearing loss and progressive visual impairment. “Clearly, it is important to know whether a child has Usher syndrome,” Smith stressed. “The rate of visual loss can actually be altered or slowed down by wearing good sunglasses—a minor intervention that can have a significant impact.” A third example, Smith cited, is Jervell and Lange-Nielsen Syndrome, in which hearing loss is associated with tachyarrhythmias, including ventricular tachycardia and ventricular fibrillation, that can lead to syncope and sudden death. “Sometimes when you think patients just have hearing loss, they don't. They may have something else that flies under the radar because it's not an obvious physical feature that is readily detectable when you look at them,” Smith added.

MORL at the University of Iowa is trying to help clinicians and patients connect these kinds of dots whenever a patient (or parent of a young patient) with hearing loss asks, “Is anything else going on? Is the hearing loss progressive?”

The lab has established an online tool on its website ( that makes it easy to determine comorbidities associated with genes associated with hearing loss. Smith's group can also prognostic the rate of progression of hearing loss. “We've taken many types of genetic hearing loss and grouped them by genetic cause. We now have large cohorts of people with the same genetic cause of hearing loss. Whether they are 5 years old or 80 years old, we plot their audiograms on one 3-D graph, with the x, y, and z axes representing frequency, decibels, and age, to generate a planar surface we call an ‘audioprofile.’ By using an audioprofile, if you are 10, you can see what your hearing thresholds are likely to be like at any age. No one has done that before,” said Smith.

“This is a great resource for everybody – patients, otolaryngologists, and audiologists,” he stressed. “Typically when patients have hereditary hearing loss, their audiograms are plotted relative to normal controls and not relative to other people with the same genetic cause of hearing loss. Now we can provide that information, which enables a person to know how severe their loss is compared to others with the same type of genetic loss.”


Smith also recognized the importance of genetic testing in enabling patients to take advantage of various gene therapies. “We are getting closer to meaningful gene therapy for humans. In terms of remediating hearing loss and preventing hearing loss, we have a fairly close time frame – perhaps three to five years,” said Smith.

Jeffrey Holt, PhD

Jeffrey Holt, PhD, professor of otology and laryngology at the Harvard Medical School, and research associate in otolaryngology and neurobiology at Boston Children's Hospital, is enthusiastic about the forward leaps being made into the field of genetics around hearing loss. “We are born with about 16,000 sensory cells in the auditory organ and when they die they are just gone. Gone for life,” he said, explaining the various routes gene therapy might take. “They die from many causes— it could be genetics, which is what my lab is focused on, but it could also be natural aging, exposure to ototoxic medications, or environmental factors like over-exposure to loud sounds from listening to an iPod too loud or working on a construction site, an aircraft carrier or playing in a rock band. Toxic noise level can damage hair cells.”

But is that damage irreparable? One clinical trial – ATOH1 – undertaken by researchers at University of Kansas, Columbia, and John Hopkins, may prove it's not.

It is already known that a master gene turns on during human development and causes a primordial cell to turn into a hair cell. “So this gene therapy for deafness is aimed at regenerating the sensory hair cells of the inner ear by using a master control gene called ATOH1,” Holt explained. “The researchers have taken a leap of faith with this strategy; they know the master cell works during development, but will it work in an older or mature ear? If they can indeed take the same gene and place it into a surviving supporting cell and cause that cell to turn into a hair cell it would be nothing short of revolutionary.”

That said, there is skepticism among some experts, including Holt. “I think it is great these researchers are pressing forward because there is much to be learned about how the inner ear works, how best to do surgeries, and deliver therapeutics to the ear. But I don't think ATOH1 will be the magic bullet.”

Holt believes that because hearing loss is multi-factorial, various “magic bullets” will be required to shoot holes into the various causes. “I think each form of deafness will require its own unique therapy – and that is where we must invoke precision medicine,” he commented. “We really have to know the cause of any person's deafness to design a precision medicine treatment or guide an intervention.”

To that end, Holt's team is taking a genetic (as opposed to environmental) approach to deafness. An estimated one out of 1,000 babies is born with genetic hearing loss, either to parents who are deaf themselves or are carriers of some gene mutation that causes deafness. “We are getting a better grasp on the genes – about 80 to 90 of them so far – that cause deafness when mutated. We think there may be a hundred more still to be identified, so work continues,” he said.

Once genes are identified, the goal is to switch them on or off in some way to compensate for or counteract the mutation. “We are investigating why mutations in these genes cause hearing loss and what we can do to restore function. Our strategy has been to take the correct form of the gene on the DNA sequence and package that into a virus,” Holt explained.

He was quick to admit that using viruses “might sound scary. But they actually contribute a long evolutionary history of getting into cells. They can ‘infect’ cells carrying genetic material. We have engineered viruses by removing the viral genes and taken advantage of their ability to infect. And the coolest part is it actually works. We dreamed up this crazy idea, put whatever DNA sequence we wanted into that virus, then let the virus do the job of carrying the DNA into the ear.”

Asked if these viruses are equipped with some sort of genetic GPS targeting ability, Holt explained, “They will infect any cell they land on. And delivering the virus to the right target is important as some of the genes they carry could conceivably be toxic to the wrong target.”

To circumvent the problem, Holt said they utilize “… a genetic trick called a DNA promoter.” In brief, a promoter is an upstream part of a gene that tells the cell whether or not to make this gene. That promoter is active in some cells and not in others. Utilizing promoters that are active in the target cells but inactive in non-target cells, Holt and his team are able to recruit them as switches to turn on gene expression in only the correct cell types.


One of the targeted gene types is called TMC1, which encodes key protein for converting molecular stimulus of sound into an electrical signal transmitted to the brain allowing for hearing. There are 40 different mutations in TMC1 that cause deafness in humans.

“We figured this was a good target, so we've tried to restore function in mice by using the correct sequence of TMC1,” said Holt. The results, published last year, “have been remarkable,” Holt said (Askew. Sci Transl Med 2015 8;7[295]:295ra108 “First, we restored function at the cellular level – cells in the inner ear began working again when the mutant cells were not working at all. Next, we restored function at the auditory systems level. We placed electrodes on the back of a mouse's head to measure the electrical activity when we played sound into an ear. A deaf ear has no response with the scalp electrode. But after treating the mouse with this gene therapy strategy, we began seeing this electrical activity when we played sounds. Finally, we used a behavioral level response. Typically when we play a sudden loud sound, deaf mice don't jump or startle. But after treating deaf mice with this gene therapy, they began to jump.”

Just as impressive is the work done since that study was published. “In that study we characterized a partial recovery – which was good, but hearing was not back to normal as those mice could hear loud sounds, not soft sounds. We've been working to perfect it and haven't even published this work yet,” said Holt with excitement. “But I will tell you that we have a new viral vector that is even better and infects 80-90% of all the sensory cells of the ear. So we can deliver the correct gene now back to 80-90% and we are getting much more complete recovery – almost back to normal hearing level. We've made huge progress in the last year. Mice are jumping all over the place…”

It will still take some time to bring this to the human world. The gene therapy will be used in pig and/or monkey ears, as well as in human ear tissue harvested from biopsies. When safety has been fully demonstrated, it will move into the human sector – likely at least five years from now.

“The message I would send to clinicians in hearing is: have your patients sequenced,” said Holt. “We still need better information around the most prevalent gene mutations so that we can target them, one by one. It's going to take some time, but we're going to keep banging away at this stuff until we solve it.”

As the answers become clear, clinicians must be prepared to embrace them. “Many clinicians have not been trained in genetics, so even if they offer genetic testing, oftentimes the results will be hard to understand,” said Smith. “Healthcare professionals must be educated to the power and value of genetic testing, and the effect it will have on the diagnostic paradigm. Today that paradigm for the evaluation of hearing loss includes CT scans, MRI, all kinds of things. But if you do genetic testing first, you will no longer need those. Genetic testing changes the diagnostic order of evaluations in persons with hearing loss. That, in turn, will save healthcare dollars. It's a win-win.

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