Gene therapy triggers growth of new auditory hair cells in mammals

Updated 2:00 PM June 16, 2003

Gene therapy triggers growth of new auditory hair cells in mammals

By Sally Pobojewski
Medical School Communications

U-M scientists have used gene therapy to grow new auditory hair cells in adult guinea pigs—a discovery that could lead to new treatments for human deafness and age-related hearing loss.

Math1 expression (orange stain) in cells in and around the sensory epithelium of the inner ear from a guinea pig after gene therapy. (Photo by Kohei Kawamoto and Yehoash Raphael, Medical School)

Healthy hair cells are vital to the ability to hear, but aging, infection, certain medications and exposure to loud noises can damage or destroy hair cells, causing sensorineural hearing loss—a condition affecting more than 30 million Americans. Since the discovery in the late 1980s that birds can regenerate damaged hair cells spontaneously, scientists have been trying to find a way to induce the replacement of lost hair cells in mammals.

U-M scientists now have accomplished this goal by inserting a gene called Math1 into cells lining the inner ear.

"We found that non-sensory epithelial cells in adult guinea pig cochlea can generate new sensory hair cells following the expression of Math1," says Yehoash Raphael, an associate professor of otolaryngology in the Medical School, who directed the study. "We also found that some of these hair cells can attract the growth of new fibers from auditory neurons."

In a normal ear, vibrations from sound waves striking the eardrum are transferred to fluid inside a snail-shaped bony organ called the cochlea, which is the auditory component of the inner ear. When cochlear fluid moves, it stimulates movement in thousands of tiny projections on hair cells lining the inside of the cochlea. Moving hair cells initiate electrical signals, which are picked up by auditory nerve fibers and carried to an area of the brain called the auditory cortex. If hair cells are damaged or missing, electrical signals are not generated and hearing is impaired.

"After embryonic development, hair cell production ceases. Unlike other epithelial cells in the skin or gut, epithelia in the inner ear contain no stem cells, so there is no source for renewal," Raphael explains. "That's the main reason why hair cell loss is permanent. When we over-expressed Math1 in non-sensory cells of the mature cochlea, however, we found that it causes them to transdifferentiate or change their personality to become hair cells."

In the next stage of research, Raphael will determine whether the guinea pig hair cells are functional and able to transmit sound signals to auditory neurons. He also plans to test the procedure in aging animals and in animals that are completely deaf.

"This is just the beginning," Raphael says. "It is really just a proof of the principle to show that, with proper gene therapy, these non-sensory cells have the competence to become hair cells."

The research was funded by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health and supported by GenVec Inc. GenVec provided its proprietary adenovector technology to deliver the atonal gene, Math1. Raphael was an occasional consultant to GenVec, but has no significant financial interest in the company.

First author on the paper was Kohei Kawamoto, a former U-M research fellow who is now at Kansai Medical University in Osaka, Japan. Co-authors on the paper include Douglas Brough, director of vector sciences at GenVec Inc.; Shin-Ichi Ishimoto, a former U-M research fellow; and Ryosei Minoda, a post-doctoral fellow in the Medical School.

Gene therapy triggers growth of new auditory hair cells in mammals

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