New cochlear hair cells formation

promises hope for humans.

by: Thomas H. Maugh II

Los Angeles Times

February 15, 2005

M ichigan researchers have restored hearing in deaf mammals for the first time, a feat that represents a major step toward the treatment of the 27 million Americans with acquired hearing loss. By inserting a corrective gene with a virus, the team induced the formation of new cochlear hair cells — the key intermediates in converting sound waves into electrical impulses — in the ears of artificially deafened adult guinea pigs. They later demonstrated that the animals responded to sounds, according to the study published Monday in the journal of Nature Medicine.

“A lot of the techniques would fairly easily translate into a clinical setting” for use in humans, said neuroscientist Matthew W Kelley of the National Institute on Deafness and Other Communication Disorders, who was not involved in the research. Humans have about 16,000 hair cells in the cochlea of each ear, where they convert sound waves into nerve impulses. The cells are easily damaged by loud noises, aging, infections and certain medications. Once damaged, they cannot regenerate on their own.

The key to the generation of new hair cells is a gene called Atohl, first discovered in fruit flies in 1998 by geneticist HudaY. Zoghbi of the Baylor College of Medicine. Variants of the gene have since been discovered in almost all species of animals. During fetal development, the gene converts some cells in the ear into hair cells. In other ear cells, called supporting cells, its activity is suppressed. Researchers then showed that, working in laboratory dishes, the gene could convert supporting cells into hair cells.

Two years ago, Yehoash Raphael and Kohei Kawamoto of the University of Michigan Medical School reported that inserting the gene into supporting cells in live guinea pigs produced thousands of new hair cells. “Everybody in the field was amazed that this worked,” Kelley said. “We thought it was going to be really hard, and that it would require a whole lot of genes. But in those experiments, the researchers did not deafen the animals first. “Truly, I was not sure it was going to work, and I didn’t see the point of going through all the extra steps to deafen them,” Raphael said. This time they did, using toxic chemicals to kill the hair cells in both ears of 10 guinea pigs. Microscopic images taken three days later confirmed that all the hair cells had been destroyed. On the fourth day, they used gene therapy with a viral vector to insert the Atohl gene into the guinea pigs’ left ears. Within two months, new hair cells had appeared in the treated ears, but not in the untreated right ears.

To determine whether the new hair cells were functional, the team used tests of auditory brainstem response to measure the guinea pigs’ ability to hear sounds. In effect, they observed increases in brain activity when they exposed the animals to noises. “The bottom line is, their hearing gets better, and that is a very big step,” Kelley said. Raphael and his colleagues are now trying to determine how good the restored hearing is. To indicate whether the guinea pigs can hear and how well, they are working with a Michigan psychologist who is an expert at training animals to display various behaviors. They are trying to determine, for example, whether the animals can differentiate between loud and soft, and between different frequencies.

They are also studying animals who have been deafened by other means, older animals, and animals that have been deaf for longer periods of time before treatment begins.  Even if all these experiments are successful, experts said, the required studies for safety and efficacy mean that it will be the better part of a decade, at least, before the technique can be tried in humans.

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