New Approach to Treat Inner Ear Hair Cell Damage and Hearing Loss in Mature Mammals

Tuesday - May 9 2023, 00:55 UTC - 1 year ago

Scientists from Harvard Medical School have developed a drug-like cocktail that activates specific genetic pathways in adult mice, enabling the formation of functioning inner ear hair cells, which is potentially capable of restoring hearing loss in humans. The Gene and Cell Therapy Institute at Mass General Brigham hopes to take this research further and offer life-changing therapies to those suffering from hearing loss.

A team of scientists from Harvard Medical School has developed a substance resembling medicine that may restore inner ear hair cells, paving the way for gene therapy clinical trials and benefitting those with hearing loss. More than 90% of people with hearing loss have sensorineural hearing loss, which is caused by the destruction and damage of the hair cells that carry sound signals to the brain.

Since they don't divide, hair cells in the inner ear are different from most other cells in the body in that they cannot regenerate. The study, published in PNAS, shows that hearing loss may be treated by reprogramming genetic pathways.

--- 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 HC progenitors to amplify their proliferation and differentiate into mature HC-like cells in vivo.