"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."
"We knew that transdifferentiation of supporting cells was a major source of new hair cell development in birds," Raphael says. "But there was no proof it would work in mammals. We started gene therapy experiments in 1994 and it took us seven years to develop a successful method of introducing the gene into the non-sensory cochlear epithelium."
Dr. Kohei Kawamoto, Ph.D., a former U-M research fellow who performed the laboratory experiments, used an adenovirus as a vector to deliver the Math1 gene to inner ear epithelial cells. Kawamoto injected the Math1 vector into inner ear fluid of 14 adult guinea pigs. The same procedure, but without the transfer of the Math1 gene, was performed on 12 matched control animals.
Thirty to 60 days after inoculation, U-M scientists used scanning electron microscopes to examine inner ears from both sets of animals. In experimental guinea pigs that received the Math1 gene, scientists found new hair cells growing in areas where hair cells are typically absent. No new hair cells were found in the control animals.
"The inner ear is an ideal target for gene therapy, because it is closed not sealed, but nicely isolated," Raphael says. "As long as the amount you inoculate is small, the spread to other organs is minimal, and the risk of systemic toxicity is almost zero."
Because the total amount of fluid in t
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Contact: Sally Pobojewski
pobo@umich.edu
734-615-6912
University of Michigan Health System
31-May-2003