Drug-Like Cocktail Used by Researchers to Regenerate Hair Cells for Hearing Loss in Preclinical Study

Effective hearing loss treatments have eluded medicine because once sensory hair cells (HCs) in the inner ear are damaged or destroyed, they cannot be regenerated. However, researchers at Mass Eye and Ear, a member of Mass General Brigham, think they may have developed a solution to address this longstanding limitation.

A team led by Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Labs at Mass Eye and Ear, reports that they have created a drug-like cocktail of different molecules that successfully regenerated hair cells in a mouse model by reprogramming a series of genetic pathways within the inner ear.

They hope their findings, “Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice,” published in PNAS, could one day pave the way for clinical trials for a gene therapy that can be administered to people with hearing loss.

“…we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cell regeneration in [wild type] mice with HC loss in vivo. Our study identifies a strategy by a clinically relevant approach to reprogram mature inner ear for HC-like cells regeneration, laying the foundation for hearing restoration by HC regeneration,” the investigators wrote.

“These findings are extremely exciting because throughout the history of the hearing loss field, the ability to regenerate hair cells in an inner ear has been the holy grail,” said Chen, who is also an associate professor of otolaryngology–head and neck surgery at Harvard Medical School. “We now have a drug-like cocktail that shows the feasibility of an approach that we can explore for future clinical applications.”

New approach to achieve hearing loss treatment

Previously Chen’s research team studied zebrafish and chickens to uncover which pathways were responsible for inducing the cell division required to regenerate new hair cells. They discovered two molecular signaling pathways, Myc and Notch, were crucial to this process. In a study published in 2019, they showed for the first time that when these pathways were activated in adult transgenic mice, remaining inner ear cells could divide and develop characteristics of hair cells. The new cells contained transduction channels that relay sound signals and the ability to form connections with auditory neurons—processes essential to hearing.

While an exciting discovery at the time, such an approach was not directly translatable to people, according to Chen. Unlike transgenic mice, humans cannot have Myc and Notch pathways turned on like a light switch. A drug therapy, he explained, would have to be introduced to the inner ear to activate the Myc and Notch pathways.

Previous studies have shown that a chemical compound called valproic acid (VPA), can activate Notch; however, no molecule exists to effectively activate Myc. That led the researchers to instead look for drug molecules that can alter the downstream pathways that turn on and off when Myc is activated.

Through single-cell RNA sequencing, they discovered that activating Myc and Notch led to a downstream effect in which two other pathways, Wnt and cAMP, became activated. Importantly they found chemical compounds that can directly activate Wnt and cAMP. They then used small biological molecules called small interfering RNAs (siRNA) to remove genes downstream that suppressed the activation of the Myc pathway.

The researchers then combined the chemical compounds and siRNA molecules into a drug-like cocktail. They delivered it to the inner ear of a normal adult mouse with damaged hair cells—an important distinction, as wildtype, non-transgenic mice would be more translatable to humans. They further delivered the gene Atoh1 by a gene therapy approach that utilizes a harmless adenovirus into the cocktail-treated inner ear. They found this drug-like cocktail combined with adenovirus turned on Myc and Notch, which led to the regeneration of new hair cells. They verified then that the hair cells were functional through advanced imaging and other techniques.

The researchers are conducting ongoing studies and refinements to this treatment approach in larger animal models, which are necessary before applying to initiate clinical trials. They noted that more research is needed to address limitations and challenges for delivering a treatment to the inner ear. They are examining different gene therapy and surgical methods.

“My colleagues and I frequently are contacted by people with hearing loss who are desperate for effective treatments,” said Chen. “If we can combine a surgical procedure with a refined gene therapy delivery method, we hope we can achieve our number one goal of bringing a new treatment into the clinic.”

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