When it comes to sensory functions, the eyes have been the focus of much attention from researchers and drug developers, resulting in last year's breakthrough for Spark Therapeutics Inc. with the FDA nod for gene therapy Luxturna (voretigene neparvovec-rzyl) to treat children and adults with confirmed biallelic RPE65 mutation-associated retinal dystrophy, an ultra-rare disease that leads to vision loss and, sometimes, blindness. (See BioWorld, Dec. 20, 2017.)

The ears, arguably of similar if not equal sensory importance, have taken a back seat in labs and clinics. But that's starting to change, thanks to growing interest by researchers in conductive and sensorineural forms of hearing loss – the two main types – along with increased curiosity about the apparent relationship between hereditary and noise-induced factors. Biopharma and investors, too, are pricking up their ears at the potential therapeutic and commercial opportunities.

Hearing, like sight, results from sensory inputs that come in pairs and are processed by the brain. Sound from the outside the body travels through the ear canal, hits the eardrum, moves the three ear bones and is transmitted as a vibration, explained Michael Hoa, otolaryngology surgeon-scientist in the auditory development and restoration program at the NIH's National Institute on Deafness and Other Communication Disorders. The last of those bones, the stapes, contacts the cochlea at the oval window – the intersection of the middle and inner ear – prompting fluid in the cochlea to move the hair cells, prompting them to send electrical signals through the auditory neuron to the brain.

Conductive hearing loss broadly results from disorders or abnormalities of the ear canal, ear drum or ear bone, Hoa pointed out, while sensorineural hearing loss involves the inner ear, the neurons that connect to the inner ear or the auditory pathways.

Although certain surgical procedures can help to remedy conductive hearing loss, treatment for sensorineural hearing loss mainly has been limited to hearing aids – which simply amplify all sound – and cochlear implants, indicated only for those with profound hearing loss.

"One of the challenges that companies and researchers have encountered in looking for treatments for sensorineural hearing loss is that we don't have a lot of treatments for people somewhere in between," Hoa told BioWorld.

Researchers 'have to make our best educated guesses'

Unlike visual impairments, which can occur and are readily apparent throughout the lifespan, hearing loss is most conspicuous in early life, when congenital forms typically are discovered in infants and young children, and during what D. Bradley Welling, professor and chair of otolaryngology at Harvard Medical School, called "the gray tsunami" that occurs with aging.

At least 50 percent of hearing loss is tied into hereditary factors, which represent a major area of study, according to Welling, who's also chief of otolaryngology at Massachusetts General Hospital and Massachusetts Eye and Ear (MEE), where he additionally serves as senior scientist. Hereditary influences are further divided into syndromic – related to a broader genetic condition – or non-syndromic forms. Other types of congenital hearing loss in early life usually are linked to traumatic damage, such as infection or antibiotic toxicity.

"There's a lot of excitement about the genetics of hearing loss," Welling told BioWorld. "We are getting closer and closer to therapeutic success with a number of different techniques where we can show the ability to protect hearing or restore hearing in some animal models – mice and guinea pigs. We haven't gotten there yet with humans – there are a lot of hurdles there – but we're getting closer."

For instance, David Liu, professor of chemistry and chemical biology at Harvard University and vice chair of the faculty and a member of the Broad Institute of the Massachusetts Institute of Technology and Harvard, and Zheng-Yi Chen, associate professor of otolaryngology at Harvard Medical and associate scientist at MEE, led a team that used of CRISPR-Cas9 technology to edit a single genetic defect – a mutation in the gene Tmc1 – in young mice to prevent progressive hearing loss that eventually would have led to profound deafness. Their work was reported late last year in Nature.

Gwenaëlle Géléoc, assistant professor of otolaryngology at Boston Children's Hospital and Harvard Medical, and colleagues showed the ability to make a similar improvement in a mouse with the same defect that's seen in Usher syndrome, a condition characterized by partial or total hearing loss and vision loss that progresses over time.

Researchers also are exploring the relationship between genetic forms of hearing loss and presbycusis – the type of gradual hearing loss that occurs in many individuals as they age. The association is "complex," Welling said and, in the case of presbycusis, likely linked to mutations in multiple genes. But it's evident to scientists that patterns of age-related hearing loss occur in families, leading to speculation that some genes may confer protective effects while others may hasten degeneration.

"Aging and genetics are not necessarily mutually exclusive," Hoa said. "We're very interested in finding treatments for people who appear to be more susceptible to the ravages of age in hearing."

In general, interpreting progress on understanding the genetic underpinnings of hearing loss can be viewed "as an optimist or a pessimist," Hoa added. "We've learned a lot about how the ear develops. We know there are some master regulatory genes," like Atoh1 – the target of a viral vector trial by Novartis AG. "But we know there's a lot more to it."

The organ of Corti, where the hair cells lie in the cochlea, "is a finely tuned, highly structured organ," he pointed out, with one row of inner and three rows of outer hair cells, plus supporting cells, allowing for the transduction of auditory signals into nerve impulses.

Although "I don't think we're there yet" in fully understanding the mechanism of human hearing, that shouldn't stop therapeutic efforts, Hoa insisted.

"In terms of advancing medicine, we often have to make our best educated guesses in certain areas because we're not always going to know every single answer along the way," he said.

More than 100 genes play a role in hearing

Even those who best understand the mechanics of the ear acknowledge they're still learning about the effects of environmental insults to hearing – mainly exposure to noise. For one, the so-called "temporary threshold shift" – measurable reduction in hearing sensitivity after exposure to loud noise from a rock concert, factory floor or nearby explosion, for instance – previously was considered benign since hearing seemed to return to baseline after a "recovery" period of hours or days. But a body of research, building on evidence first published in 2009 by Sharon Kujawa and M. Charles Liberman, has shown conclusively that such damage isn't truly "temporary." Instead, Welling explained, following such noise exposure "the connections between the nerve and the inner ear get knocked in a way that is permanent, and those connections between the inner ear hair cells and the nerves don't regenerate on their own."

Kujawa, associate professor of otolaryngology at Harvard Medical and director of audiology research at MEE, and Liberman, professor and vice chair of basic research in the department of otolaryngology at Harvard Medical and director of the Eaton-Peabody Laboratories and senior scientist at MEE, published their initial findings in the Journal of Neuroscience.

Although other hair cells in the inner ear recover, and audiograms suggest that an individual's hearing returns to baseline, the real-world consequence is that people have more trouble distinguishing particular sounds, like conversations, from background noise. That lesson was brought home to Welling in the aftermath of the 2013 Boston Marathon bombing, when his MME clinic treated scores of individuals who presented with "hidden" hearing loss despite audiogram results in the normal range.

Hearing loss affects some 360 million people in the world, according to Welling, including 15 percent of adults in the U.S., so having the ability to deliver a genetic fix to the inner ears of individuals with hereditary forms of hearing loss could greatly reduce the impact of the condition. That's no easy task, however. Researchers have identified more than 100 genes that play a role in hearing – others may remain undiscovered – but they don't yet understand the importance of most of those genes or their relationships with each other.

"We have to be a little more aggressive about getting to the underlying cause of hearing loss, especially in young people," Welling said. "With such a large number of genes, we have to be fairly clever about how we target the inner ear. We can't just put something in the ear that grows hair cells in animals without knowing specifically whether In humans that's the underlying problem or whether it's the way the nerves connect to the hair cells in the inner ear."

'Biopharma is getting invested'

The use of viral vectors to deliver gene therapies also needs refinement for use in treating hearing loss. Although certain technology shows "beautiful expression" in different parts of the inner ear, Welling said, some of the genes are too large to place in a single vector to deliver to the appropriate site.

Questions that have dogged gene therapy efforts in other indications – how much genetic material is needed to effect a treatment or cure, which of dozens of distinct cell types to target and how long the protective effect will persist, for instance – also remain unanswered in hearing loss.

Still, "the more specific we are in understanding the deficits in hearing, and the better we target the source of the problem, the more likely we'll be to resolve these issues," Welling said. For instance, individuals with repetitive noise-induced damage, whether from military service or overuse of wireless earphones, may be helped by the placement of neurotrophic growth factors into the cochlear synapses to reconnect the nerve fibers and inner ear hair cells, he suggested.

Other promising therapeutic approaches include the use of small molecules to curb or correct hearing loss and, longer term, regeneration of inner ear hair cells.

Researchers have accelerated their efforts by eschewing the trial-and-error method of drug hunting and turning to large throughput screening to test hundreds of FDA-approved compounds simultaneously on inner ear organoids to learn "which one of those drugs move those cells toward better hearing as opposed to poorer hearing," Welling said. Although the jury still is out on how well inner ear organoids can predict which small molecule, gene and other therapies will work in humans, moving preclinical testing from animal to human models likely will result in better success rates in the clinic, Welling said.

Despite the challenges, "I'm excited about the progress that we've made," he emphasized. The effort to address hearing loss therapeutically has ignited interest in researchers around the globe, and "biopharma is getting invested," Welling added. "They also see the great tsunami and realize there are a lot of individuals who are affected and could benefit from a treatment or cure. The level of interest has skyrocketed."

Hoa agreed.

"Biopharma is very important in translating basic science and these early studies into trials that can be done in humans, and a number of companies are very interested in this field," he said. "It's an exciting area of collaboration between biopharma and the scientific community."

Editor's note: Part II looks at the pipeline of candidates and early stage prospects to treat hearing loss.