Posted July 19, 2023

Zheng-Yi Chen, D.Phil., Massachusetts Eye and Ear Infirmary, Harvard Medical School

Hearing loss is one of the most common disabilities among Veterans. According to the Veterans Benefits Administration, more than 1.4 million Veterans are affected by service-connected disability due to hearing loss.¹ Although hearing loss affects people of all ages, currently there are no U.S. Food and Drug Administration-approved drugs available to restore lost hearing. Most hearing loss occurs due to damage to or loss of cochlear hair cells (HCs) in the ear; these cells are responsible for turning sound into electrical stimulation that is perceived by the brain. Once these cells are damaged or lost in mammals, they are unable to regenerate on their own, making hearing loss permanent.

With a Hearing Restoration Research Program fiscal year 2017 (FY17) Translational Research Award and an FY20 Focused Research Award - Funding Level 2, Dr. Chen’s team developed a potential therapy to restore HC cells and tested it in adult mice. Much like stem cells, supporting cells (SCs) in the ear can grow to become other cell types, but when fully mature in mammals, they no longer have this ability. The team’s strategy focused on reprogramming SCs to regain their ability to develop into new HC-like cells to restore hearing. The team first used genetic engineering approaches to activate two SC genes, Myc and Notch1, in mouse cochlea cultured in the lab. Active Myc and Notch1 are involved in the signaling pathways in SCs that enable these cells to develop into HCs. This approach allowed Dr. Chen’s team to introduce extra copies of Myc and Notch1 genes directly into SCs and activate them with a signaling molecule, Atoh1. With this approach, the team successfully reprogrammed SCs to develop into HC-like cells.

After determining the effectiveness of this strategy, the team developed a new method for SC activation that does not require genetic engineering, as this approach is not feasible for patient treatment. They developed a method that used a drug-like mixture of small molecules to modify SC development; this mixture could be added into the culture with the adult mouse cochlea explant. The first component activates the Notch1 gene already present in SCs, while the second component blocks repressors of the Myc gene, effectively activating Myc. In models of non-engineered mouse cochlea, this mixture was able to reprogram SCs to develop into new HC-like cells, although with less efficiency than in the engineered models.

To improve the efficacy of the small molecule drug-like mixture, the team explored other genes that might be involved in SC reprogramming. They identified two additional molecules, Wnt and cAMP, that are necessary for reprogramming of SCs, and added activators of these to the small molecule mixture to produce a cocktail. In all experiments, this cocktail was delivered to the cochlear cells to restore their developmental potential followed by viral-delivered Atoh1. The cocktail and Atoh1 treatment triggered regeneration of HC-like cells at a rate similar to that seen in the genetically engineered models, revealing that Wnt and cAMP activators improved its activity.

After showing the improved activity in culture, the team tested the cocktail’s efficacy using in vivo mouse models in which hair cells were killed by antibiotics gentamycin. Compared to control mice that did not receive the treatment, cocktail-treated mice had significantly more HC-like cells in the inner ear, and these cells originated from the conversion of the reprogrammed SCs.

Dr. Chen’s team will conduct the study to restore hearing in deaf mice by HC regeneration. A more precise control of HC regeneration will be needed, including the regenerated HC in the correct location in the ear to allow them to conduct the electrical signals pertinent to hearing restoration and to improve the maturation of regenerated HC. The team also aims to find an efficient but minimally invasive method for cocktail delivery that is clinically applicable. With these preliminary study results, Dr. Chen’s team has proved that a cocktail can be delivered into the ear to stimulate HC regeneration in adult mice, a strategy that may translate to the restoration of lost hearing in humans.

References:

¹ Veterans Benefits Administration Annual Benefits Report, Fiscal Year 2022. 2023. Veterans Benefits Administration. U.S. Department of Veterans Affairs. https://www.benefits.va.gov/REPORTS/abr/docs/2022-abr.pdf

Publications:

Quan YZ, Wei W, Ergin V, et al. 2023. Reprogramming by drug-like molecules leads to regeneration of cochlear hair cell-like cells in adult mice. Proceedings of the National Academy of Sciences of the United States of America 120(17):e2215253120. https://doi.org/10.1073/pnas.2215253120

Links:

Public and Technical Abstracts: Hair Cell Regeneration in Mature Mammalian Inner Ear
Public and Technical Abstracts: Hair Cell Regeneration and Treatment for Noise-Induced Hearing Loss in Pig Model

Top of Page