https://hms.harvard.edu/news/scientists-regenerate-hair-cells-enable-hearing Skip to main content Mobile Main Navigation * Education & Admissions + Medical Education + MD Admissions + Master's Degree Programs + PhD Degree Programs + Online Learning (HMX) + Postgraduate Education + Corporate Learning + Graduation + Registrar + Health Info * Research + Research Departments, Centers, Initiatives and more + Blavatnik Institute + Postdoctoral Training + HMS Researcher Resources + Countway Library of Medicine + Paper Chase * News & Events + News + Harvard Medicine magazine + Multimedia + Calendar + Sign Up for Email Communications + For Media + Publications Archive * About HMS + The History of HMS + Campus and Culture + Diversity and Inclusion + Facts and Figures + HMS Affiliates + LCME Accreditation + Leadership + Contact HMS + Office of the Dean + People of Harvard Medical School * Keep HMS Healthy + Harvard COVID-19 Information: Keep Harvard Healthy + Community Messages + HMS Flexwork Initiative + Verify Your Vaccination + Harvard University Health Services + HMS Responds to Coronavirus + COVID-19 Advisory Team Mobile Utility Navigation * Teaching Hospitals & Affiliates * Departments & Offices * Dental Medicine * Harvard University * Giving [logo] Menu Utility Navigation * Teaching Hospitals & Affiliates * Departments & Offices * Dental Medicine * Harvard University * Giving Search Main navigation * Education & Admissions + Medical Education + MD Admissions + Master's Degree Programs + PhD Degree Programs + Online Learning (HMX) + Postgraduate Education + Corporate Learning + Graduation + Registrar + Health Info * Research + Research Departments, Centers, Initiatives and more + Blavatnik Institute + Postdoctoral Training + HMS Researcher Resources + Countway Library of Medicine + Paper Chase * News & Events + News + Harvard Medicine magazine + Multimedia + Calendar + Sign Up for Email Communications + For Media + Publications Archive * About HMS + The History of HMS + Campus and Culture + Diversity and Inclusion + Facts and Figures + HMS Affiliates + LCME Accreditation + Leadership + Contact HMS + Office of the Dean + People of Harvard Medical School * Keep HMS Healthy + Harvard COVID-19 Information: Keep Harvard Healthy + Community Messages + HMS Flexwork Initiative + Verify Your Vaccination + Harvard University Health Services + HMS Responds to Coronavirus + COVID-19 Advisory Team News & Research Scientists Regenerate Hair Cells that Enable Hearing Researchers move closer to gene therapy solution for hearing loss By RYAN JASLOW | Mass Eye and Ear April 19, 2023 Research 6 min read Close up view of a woman's left ear Image: Jun/iStock/Getty Images Plus Hearing loss affects about 48 million Americans and 430 million people worldwide, with those numbers expected to grow as populations age. More than 90 percent of individuals affected have sensorineural hearing loss, caused by damage to the inner ear and the destruction of the hair cells responsible for relaying sounds to the brain. Get more HMS news here Hair cells cannot be regenerated in mammals, including humans, because unlike other cells in the body, any remaining hair cells in the inner ear cannot divide and other inner ear cells cannot convert themselves into new hair cells. Species like fish, birds, and reptiles, however, possess this ability. Related Stories The Hearing Molecule The exquisitely complex process of hearing begins with the opening of a tiny molecular gate The snail-shell-shaped part of the inner ear that houses hair cells Reversing Hearing Loss Reprogramming enables regeneration of inner-ear cells Illustration of sound wave and ear Estimating Hidden Hearing Loss New word-score model leads to better evaluations of cochlear nerve damage back of the head of a white grey-haired man holding a finger to his ear that has a hearing aid Hidden Hearing Loss Revealed Two biomarkers of brain function can measure the ability to follow conversations in noisy environments photo of side of man's head showing sound wave near ear For this reason, effective hearing loss treatments for humans have eluded medicine, and the loss of hair cells, which can be caused by aging, noise exposure, and other factors, renders an individual's hearing loss permanent. Now, Harvard Medical School scientists at Mass Eye and Ear are hopeful they've developed a solution to address this longstanding limitation. A research team led by Zheng-Yi Chen, an HMS associate professor of otolaryngology and associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear, reported creating 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. The researchers hope their novel findings, published April 17 in PNAS , could one day pave the way for clinical trials for a gene therapy that can be administered to people with hearing loss. "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. "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 that two molecular signaling pathways, , were crucial to this process. In a study published in 2019, the team 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. Trusted health and wellness information From Harvard Health Publishing Sign up for our free HealthBeat newsletter 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 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 (siRNAs) to remove genes downstream that suppressed the activation of the Myc pathway. "Think about a brake when driving a car," explained Chen. "If the brake is always engaged, you can't drive. We found an siRNA that could remove the brake in this genetic 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 wild-type, 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. Remarkably, 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 that the hair cells were functional through advanced imaging and other techniques. Regenerating hair cells through gene therapy approach Studies like Chen's show the promise of gene therapy for treating incurable conditions like hearing loss. Last year, this research project was selected out of hundreds as one of the Disruptive Dozen gene and cell therapy technologies most likely to have a significant impact on health care over the next several years at the Mass General Brigham World Medical Innovation Forum. Mass General Brigham recently launched its Gene and Cell Therapy Institute to help translate scientific discoveries made by researchers like Chen into first-in-human clinical trials and, ultimately, life-changing treatments for patients. 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 note that more research is needed to address limitations and challenges for delivering a treatment to the inner ear. Scientists are examining different gene therapy and surgical methods, including an approach previously honed at Mass Eye and Ear, in which a different viral vector called an adeno-associated virus (AAV) was able to precisely and safely deliver gene therapy to the inner ear through a novel surgery. Similar AAV-surgical approaches are currently used at Mass Eye and Ear in approved and experimental drug therapies for patients with inherited retinal disorders that can lead to blindness. "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." Authorship, funding, disclosures Co-authors of the study include Yizhou Quan, Wei Wei, Volkan Ergin, PhD, Arun Prabhu Rameshbabu, Mingqian Huang, ChunJie Tian, Srinivas Vinod Saladi, and Artur Indzhykulian, of Mass Eye and Ear. This study was funded by the National Institutes of Health (NIH grants R01DC006908, R01DC016875, R56DC006908, UG3TR002636, and R01DC017166), the Department of Defense (DOD grants W81XWH1810331, W81XWH2110957), the Fredrick and Ines Yeatts hair cell regeneration fellowship, Harvard Catalyst Translational Innovator Program The Five Senses, and the Mike Toth Head and Neck Cancer Center. Chen is a co-founder and a SAB member of Salubritas Therapeutics, which is developing treatments for hearing loss including genome editing, inner ear regeneration, novel delivery, and gene therapy, and has ownership of over 5 percent equity. Quan and Chen are co-inventors on a patent application that has been filed based on this study. A patent application on the combination of small molecules/siRNAs in hair cell regeneration has also been filed. Adapted from a Mass Eye and Ear news release. Related News Illustration in pink of the anatomy of the pancreas AI Predicts Future Pancreatic Cancer May 8, 2023 An AI tool identified people at the highest risk for pancreatic cancer up to three years before... Group of medical students in Vietnam looking on as a baby is examined in clinic, held it its mother's arms. Trust and Global Partnerships May 5, 2023 What HMS is learning from a 20-year effort to strengthen Vietnam's health care system Out-of-focus photo of ER nurse checking an IV bag with a surgeon looking at a patient on a gurney behind her Can TV Shows Change Health Care? 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