Regenerated inner ear hair cells in mice provide new hope for those with hearing loss

New approach to hearing loss treatment

A team of researchers led by Zheng-Yi Chen, an associate professor of otolaryngology at HMS and an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear, observed zebrafish and chickens to identify the molecular signaling pathways that promote cell division and the growth of new hair cells. They discovered via their studies the vital function the Notch and Myc molecular signaling pathways served in this process. 

The scientists activated these pathways in adult transgenic mice in 2019, which caused the division of the remaining inner ear cells and the formation of hair cell characteristics. These cells had the ability to link with auditory neurons and transduction channels for transmitting sound signals.

The researchers' most recent study used single-cell RNA sequencing to find that activating Myc and Notch activated the Wnt and cAMP pathways downstream. They next discovered substances that directly stimulated Wnt and cAMP, and they employed small interfering RNAs (siRNAs) to silence genes downstream that prevented the Myc pathway from being triggered. 

“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.”

They then created a drug-like cocktail using these chemicals and siRNA molecules, which they delivered to the inner ear of a healthy adult mouse with damaged hair cells.

Regenerating hair cells through gene therapy

Advanced imaging techniques showed that the activation of Myc and Notch by a drug-like cocktail and adenovirus resulted in the regeneration of functioning hair cells. To get over restrictions and difficulties in administering this medication to the inner ear, more research is required. In order to safely and precisely deliver gene therapy to the inner ear, a unique operation that uses adeno-associated viruses is being investigated by scientists. This procedure was originally developed at Mass Eye and Ear. 

The Gene and Cell Therapy Institute at Mass General Brigham hopes to offer patients life-changing therapies by putting scientific breakthroughs like Chen's into first-in-human clinical trials. Before beginning clinical trials, this therapy strategy will continue to be studied and improved in larger animal models.

The study was published in the journal PNAS.

Study Abstract: 

Strategies to overcome irreversible cochlear hair cell (HC) damage and loss in mammals are of vital importance to hearing recovery in patients with permanent hearing loss. In mature mammalian cochlea, co-activation of Myc and Notch1 reprograms supporting cells (SC) and promotes HC regeneration. Understanding of the underlying mechanisms may aid the development of a clinically relevant approach to achieve HC regeneration in the nontransgenic mature cochlea. By single-cell RNAseq, we show that MYC/NICD “rejuvenates” the adult mouse cochlea by activating multiple pathways including Wnt and cyclase activator of cyclic AMP (cAMP), whose blockade suppresses HC-like cell regeneration despite Myc/Notch activation. We screened and identified a combination (the cocktail) of drug-like molecules composed of small molecules and small interfering RNAs to activate the pathways of Myc, Notch1, Wnt and cAMP. We show that the cocktail effectively replaces Myc and Notch1 transgenes and reprograms fully mature wild-type (WT) SCs for HC-like cells regeneration in vitro. Finally, we demonstrate the cocktail is capable of reprogramming adult cochlea for HC-like cells regeneration in WT 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.