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Decibel Therapeutics' study on inner ear cells may spur hearing-loss therapies

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Decibel Therapeutics' study on inner ear cells may spur hearing-loss therapies

Research funded by Decibel Therapeutics Inc. and Johns Hopkins University points to a new target in the search for better treatments for hearing loss, for which there are no approved medicines in the U.S.

The field has traditionally focused on hair cells in the ear, Decibel Therapeutics head of biology Joseph Burns said in an interview. However, the neurons connected to the hair cells may provide more nuanced explanations of damage that can diminish the ability to process sound.

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Source: Cell

Hearing loss affects 466 million people globally as of 2018, according to the World Health Organization, and ranges from congenital deafness to balance disorders to age-related hearing loss. There are currently no U.S. Food and Drug Administration-approved medicines to treat these conditions. Cochlear implants and hearing aids made by companies such as Australia's Cochlear Ltd. and Switzerland's Sonova Holding AG are the main available remedies for hearing-loss disorders.

Burns and his colleagues used a technique known as single-cell RNA sequencing, which examines the genomes or RNA molecules of individual cells, to uncover the molecular differences between neurons in the ear.

Using this technique, the research, published in the journal Cell on Aug. 2, revealed which genes were on and off in a given hair cell or neuron. Decibel's single-cell RNA sequencing platform, Burns said, allowed them to look across the inner ear's entire cochlea, which contains the hair cells connected to neurons that react to sound vibrations, as well as each cell type's response.

The main drawback of implants, Burns said, is the lack of diversification and accuracy in the electrical signals that stimulate hearing.

"A cochlear implant is not going to provide the proper signals that are necessary to get these neurons to differentiate correctly," Burns said. "It really needs to be a single hair cell connecting to a single neuron to get that diversification, whereas a cochlear implant is just throwing electrical activity at all of the neurons at once."

The updated research, he continued, may also help optimize existing cochlear implant performance.

According to Burns, the key differences discovered were three types of neurons that process sound. One of these, if damaged, would affect the ability to distinguish a specific person talking amid background noise, called "noise fidelity."

"The neurons in your ear are actually responsible for turning down that background noise and focusing on what the person who's talking to you is saying," Burns said. Losing one of those neurons would result in losing that ability to detect speech in noise, which is called hidden hearing loss. Hidden hearing loss can lead to further hearing damage, especially with age.

Burns said that one subtype of these neurons is also linked to tinnitus when damaged by loud sound.

"Basically what happens there is, those neurons are usually providing input to the brain, even in background, when there's not that much noise being played, and if you sever that connection to the brain, the brain actually tries to turn up the volume in the absence of that signal," Burns said.

Another area of focus, based on the study, is a genetic mutation that affects the hair cell's ability to detect sound. Burns said the mutation, which results in neurons not diversifying properly, is the same as the mutation that leads to congenital deafness.

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Therapeutics that arise from the research will have to first account for restoring neuronal differentiation and assuring that the restored functions match those of normally developed hair cells, Burns said. Decibel Therapeutics Chief Scientific Officer Michael Su, who co-wrote the study, said gene therapy could be a strong pathway for correcting mutations and damage — as long as there is a proper understanding of the impact of transmission to the brain.

Su also said CRISPR gene editing technology is promising and is an area that Decibel is actively exploring.

Decibel, based in Boston, is one of several companies pursuing hearing-loss treatments. San Diego-based Otonomy Inc. is testing a drug for tinnitus, and Swiss biopharma giant Novartis AG began patient trials for gene therapy and hearing loss in 2014.

Decibel has said they aspire to be the world's leading hearing therapeutics company as pioneers of the field, based on this preclinical research and other resources. The company has partnered with Regeneron Pharmaceuticals Inc., which allows Decibel to bring in Regeneron scientists to aid with areas in human genetics, animal modeling and therapeutic development. Decibel is backed by Google Ventures in addition to Regeneron.

Director of corporate development Christopher Hren said hearing loss "historically had a stigma associated with it," and this is an issue that "takes a village." Nevertheless, he said, they aspire to "lead the charge" in hearing loss.

Su said Decibel expects to have clinical candidates in human trials by 2019 while continuing active, ongoing programs in gene therapy.