Breakthrough in Hair Cell Regeneration?
Editor: An animal's ability to regenerate damaged or destroyed
auditory hair cells seems to be the key to restoring lost hearing. Some
birds routinely generate these cells, while scientists have never seen
it happen in mammals - until now. Scientists at the University of
Michigan have used gene therapy to grow new auditory hair cells in adult
guinea pigs. This doesn't mean that you can visit your doctor for this
treatment next week, but it is a major milestone on the road to new
treatments for hearing loss.
Here's the story from EurekAlert, DC - May 31, 2003
(http://www.eurekalert.org/pub_releases/2003-05/uomh-gtg052703.php)
BTW, we've been following the hair cell regeneration story for quite
some time. For some history, have a look at:
http://www.hearinglossweb.com/Medical/cures/hair/hair.htm
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Contact: Sally Pobojewski
pobo@umich.edu
734-615-6912
University of Michigan Health System
Gene therapy grows new auditory hair cells in mammals
ANN ARBOR, MI - University of Michigan 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.
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 over 30 million Americans. Since the discovery, in the late
1980s, that birds can spontaneously regenerate damaged hair cells,
scientists have been trying to find a way to induce the replacement of
lost hair cells in mammals.
U-M scientists have now accomplished this goal by inserting a gene
called Math1 into non-sensory epithelial cells lining the inner ear.
Results from the study will be published in the June 1 issue of the
Journal of Neuroscience.
"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, Ph.D., an associate professor of
otolaryngology in the U-M 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.
"During the embryonic stage of an animal's development, hair
cells and supporting cells have a common origin. Cells that express
Math1 are fated to become hair cells, while Math1 expression is
inhibited in the remaining non-sensory cells," Raphael says.
"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 the inner ear of a guinea pig is
so small, the mechanical impact of injecting the viral vector fluid into
the cochlear fluid damaged some of the hair cells in experimental
animals. "While this is a concern, we believe the micro-injection
technology can be improved to prevent this mechanical trauma,"
Raphael says. "The human cochlea is larger than a guinea pig
cochlea and may better tolerate the inoculation. Also, profoundly deaf
human candidates for this gene transfer approach would likely have
severe pre-existing hair cell loss to begin with, so the risk of
mechanically-induced side effects would be somewhat less
troubling."
One of the most surprising results of the study was the discovery of
long, slender nerve fibers growing toward some of the newly formed hair
cells. "This suggests that these hair cells can provide signals to
attract axons and that neurons can respond to these signals,"
Raphael says.
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, Ph.D., a former U-M
research fellow who is now at Kansai Medical University in Osaka, Japan.
Co-authors on the paper include Douglas E. Brough, Ph.D., director of
vector sciences at GenVec, Inc.; Shin-Ichi Ishimoto, Ph.D., a former U-M
research fellow; and Ryosei Minoda, Ph.D., a post-doctoral fellow in the
U-M Medical School.
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Contact: Sally Pobojewski, pobo@umich.edu or 734-615-6912 Nicole
Fawcett, nfawcett@umich.edu or 734-764-2220.
