June 01, 2003
Gene Therapy Grows Inner Ear Hair Cells In Guinea Pigs

Age and exposure to loud noises can damage the inner ear cochlea hair cells that grow the fine cilia hair that are used to measure sounds. Recently some scientists at the University of Michigan have succeeded in using gene therapy delivered by adenovirus vector into the cochlea to add a gene called Math1 to cells in that area that stimulates those cells to become hair cells. Math1 gene theapy has resulted in the growth of hair cells in the cochlea and nerves were detected growing toward those hair cells.

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.

This result demonstrates how gene therapy can be used to repair one kind of damage caused by injury and aging. It will take several years to turn this into a safe and useful human gene therapy. However, it seems likely that within 10 or at most 20 years deafness caused by cochlea hair cell death will be a curable disorder.

Share |      Randall Parker, 2003 June 01 01:27 AM  Biotech Therapies


Comments
Patrick said at November 4, 2003 9:15 AM:

I am currently at school in England. I am 14 years old and I have a profound hearing impairment, I find it fascinating that in a few years time there might be a chance that I would be able to have much better hearing. I have read the whole above article and I wondered how long ago this was published and if there are any improvements since then. I enjoy listening to music though I cannot make out the words, and I feel confident that in the future I will.

Truce Trujillo said at November 20, 2004 9:15 PM:

I am current welder and I read your article about the gene for hair loss. I would love to know more information about this gene, I ve always want to get my hearing back, I ve been deaf since I was 3 years old and I ve always hate my life cuz of the deafness. I would love to be able to hear again! Please contact me and update with all information or study or result with the gene study. Thank you

Lillian Francis said at December 28, 2004 3:03 PM:

I just found out about the hair cell regeneration and I am hoping that a success might come through for me because I was deaf at age 9 and I would love to get my hearing back because I am sick and tired of my life been unable to hear things clearly

Mike Clement said at January 16, 2005 2:24 PM:

Interesting stuff! I am optimistic that individuals with hair cell damage would be able to restore hearing. I have been profoundly deaf since birth and I have been keeping an eye on this stuff. I have opted out of cochlear implants as I believe that a less invasive and better solution could be found.

Anne Pounds said at February 14, 2005 8:20 PM:

I have suffered a severe hearing loss in one ear within several hours of having an IV antibiotic called gentamycin administered during surgery for a total knee replacement. Is is possible that you will be conducting human trials that I may participate in?

Beth Eilers said at June 10, 2005 11:56 AM:

Hi,I have tinnitus,but fairly normal hearing.I have been told that I don't have dead hair cells as my hearing is fine.Could some damage to this area,nerve or hair cells cause this buzzing? There have been so many theories.It sounds like this could help with the tinnitus.Is that true?HOw long before this can be utilized in humans?Thank you,Beth Eilers

Beth Eilers said at June 10, 2005 11:56 AM:

Hi,I have tinnitus,but fairly normal hearing.I have been told that I don't have dead hair cells as my hearing is fine.Could some damage to this area,nerve or hair cells cause this buzzing? There have been so many theories.It sounds like this could help with the tinnitus.Is that true?HOw long before this can be utilized in humans?Thank you,Beth Eilers

manoj naik said at June 16, 2005 1:11 AM:

Dear Sir / Madam ,

My doughetr was 8 months old and after checkup we found she has serios hearing loss . Doctor's sayes some problem in inner ears .

so , can u suggest me what i do now . can she hear ?

how can she hear , please hemp me .


thanks

Manoj Naik
Century Rayon Colony
C2/26 , Murbad Road ,
Shahad , kalyan ,
Thane - 421103
India

Mobile : +919422355961

gaurav said at July 10, 2005 12:41 AM:

My doughetr is 12months old and after checkup we found she has profound hearing loss . Doctor's says the hair cells are damaged.

so , can u suggest me what i do now . can she hear ?

NITIN TANEJA said at July 15, 2005 7:16 AM:

Hi, i am suffering hearing loss from my childhood. it has been always difficult to deal with hearing loss which is consititute it's existence with damage inner hair cells, tinnitus, and a problem called as speech discrimination. somehow i have managed to live without standanderized hearing. I always been dreaming a normal life but due to not availability of any cure, any thing in medical science and in any other science to recover this kind of problem as i have tried and observe everywhere. Now at the age of 24 after this prediction of gene therapy i am too with my other friends as posted their article over here hope too thatin nearfuture we may get relief from inner hair cells problem and will can live normal as others are living but as i have been looking reseachs from different places of world scientists that they would recover inner hair cells from a long time i am now waiting their implementation because its been a long time i am waiting and see what happens in near future...

Thanking you for reading
NITIN TANEJA
INDIA

Jay A. Kelley said at August 18, 2005 5:40 PM:

I suffer from a perilymphatic fistula. This has cost me 90% hearing in the right ear and 60% in the left with CONSTANT ringing. For those that do now know:

When fluid spills from the inner ear to the air cavity of the middle ear, it causes vertigo and sometimes hearing loss. I had both.

My hearing loss has had a major impact on my life and I would go to any lenghts to get it back.. Please keep me informed of any developments.

Jay A. Kelley
St. Louis MO

Beth Eilers said at September 4, 2005 8:28 PM:

Hi,I wrote to you in June.Is there someone who can give me more info on this?My e-mail is posted on the sight. Thank you.

Andi said at January 24, 2006 5:01 AM:

Hi Folks,

i am looking for this topic since three years. It will take may be two decades until someone found e method to make ist usable for human beeings.
Sience is a long proces, and no one will know if it works out in the END.

But it is fascinating that some people still work on the PROP. The main question is, ift it works, how can they hadle a clincal tratmend in humans...

Beth Eilers said at April 3, 2006 2:57 PM:

Hi,I have e-mailed twice in the past regarding tinnitus.Is there a direct contact number or e-mail for this organization?If so I would like more information about this procedure.Thank you,Beth Eilers

Scott A. Bennett said at April 30, 2006 8:16 AM:

hello, i have hearing loss in both ears over the years from loud music and occupational effects,loud machinery. i have just discovered this technology and will be following for future human use, but would love to be contacted regarding trials, etc...i have recently heard of a woman who had a little hammer bone in her ear replaced with a synthetic one b/c the original had become mucked up with wax, dirt, etc. friends say she can hear clearly now. is this for real? thank you and keep me posted if possible!
scott

Jonathan B. Lewis said at July 26, 2006 10:03 AM:

Just doing some research on treating tinnitus... whether there are updates on research or breakthroughs regarding gene therapy. For hearing loss... etc.

Thanks,

Jonathan B. Lewis

Jane Draughon said at December 7, 2006 7:30 PM:

My heart goes out to these young people seeking hearing solutions. I am 65 years old and am now experiencing hearing loss in the opposite register from my original hearing loss==Double trouble= I had radiation therapy on my throat as a child. Not only did it not help my post-nasal drip, it caused many other problems==Thyroid pre cancerous nodules with removal of half my thyroid gland to name a common one. Several years ago I read an article that stated people who had this radiation therapy on their throat suffered from getting choked easily due to the cilia being burned off during the treatment. I had experienced a lot of this choking if something touched the back of my throat. Is is possible that the ear cilia could also be missing? I started losing my hearing at sixteen, it got progressively worse until I started wearing a hearing aid in my forties. Now I wear two digitals, but still miss out on so much. Thank God for the person who invented closed caption. I try to make myself listen rather that read, but it can become so tiring. A hearing person could never guess how much energy can be expended trying to hear. I would certainly volunteer as a human guinea pig for regrowth of cilia When you get to the trials please sign me up.

Frank Rice said at July 31, 2007 6:19 PM:

I am 70 years young and will be scheduled for a cochlear implant later on during the year. I was told that the Nucleus Freedom implant is the best device now on the market. I would like to know if you agree with this or if there is a better product out there for me. I would appreciate any information you can give me and possible someone who may have had this implant with Nucleus Freedom could let me know how it works out for them.

Jeff said at November 24, 2007 5:08 PM:

i'm 22 and am already noticing hearing loss beacause of stupid decisions with my ipod and not protecting my heairng during maintenance work. I would gladly volunteer myself for trials of this new drug or whatever it is.

Marconi said at July 25, 2008 12:11 PM:

Well, it seems like I ain't the only one what has problems. However, I am glad that someone out there is trying to find a cure for hearing loss. I'm 25 and I had a moderate hearing loss as well. I really look forward in hearing more from this research, maybe even sponsor or find more sponsors.
Keep up the good work and I do have my fingers crossed for the sucess of such treatment.

dave mouton said at November 17, 2008 12:14 AM:

Dave Mouton: Speed the development of biotechnology solutions for hearing loss. I am working to invest as much as possible in finding some advanced techniques for improving hearing. moutonda@yahoo.com

STEPHEN TAYLOR said at April 2, 2009 11:32 AM:

HI im 41yrs old, iv'e been deaf since early childhood. i started off partially deaf , im now classed as severly . Iv'e read and seen on news medics have unveiled a pioneering stem cell treatment. I also know trials on animals have already begun and therapy could soon be tested on humans . Would you please consider me as a human guinea pig, as i would love to be able to hear again. please respond

Regards

stephen taylor

wongtanlim said at June 23, 2009 8:59 AM:

hi all

There are advances in gene theraby and in stem cell theraby. Let's be patient and wait and meanwhile continue to do things we like to do.

Regards

wongtanlim3@yahoo.com
Singapore
23.6.09

gerald e. franklin said at February 3, 2010 9:59 AM:

yes,I lost my hearing back in 1995 in my right ear,I've heard theres a pill coming out that will make inner ear hair grow, is this true. gerald e. franklin/jerryed48@aol.com

EMA said at February 9, 2010 6:53 PM:

About 4 years ago a chiropractor manipulated my neck and within a few minutes after that I experienced hearing loss. It got a bit better in about 2 weeks and has since stayed the same and my hearing loss in permanent. I can hear, but the hearing in that ear is muffled and I have a hard time hearing when there is any background noise. I don't know if the hairs are affected or not. Nobody I have talked to, including an ear, nose and throat specialist I saw, has heard of this and doesn't know how I could have lost my hearing from this. I had never had any problems with my hearing until the chiropractor manipulated my neck. I wonder if Math1 gene therapy can help me. I would love to hear from somebody.

Me said at February 23, 2010 8:15 PM:

Hi, Im 14,I may be young, but I beleive that I may have stumbled across something incredible. I was born moderate-severe bilateral hearing loss. I have spent the last 2 years constantly researching, having sleepless nights trying to solve the puzzle of hearing loss. I am a staight a-plus student even with my hearing loss, and I always try my hardest. I have thought up two theories. 1) complete replacement of the cochlea with a pacemaker-like machine that would convert sound waves into electricalneuro impulses and then transmit them to the brain. 2) Gene therapy: I have read about this new bacteria that caused regeneration of cilia. it is called Tetrahymenea. I think that administering this bacteria to newborns would cause a substantial decrease in newborns w/ hearing loss. I will forever try to solve this mystery, and I hope to have normal hearing one day.

Bob Badour said at February 23, 2010 8:21 PM:

Medical technology is reaching a point where you have a good shot at it (if nobody beats you to it.) Good luck to you!

Anonymous said at August 11, 2010 5:18 PM:

Me said at Augsut 11, 2010 at 8:13pm:

Hello, I am 35, I am current read your article about the gene for hair loss. I would love to know more about this new gene or else. I have always want to hear a words or listen to family's talking in conversation. I have been loss hearing since I was 2 year old to became hard-of-hearing with digtial hearing aid but not enought!I always been dreaming a normal life to able hear again to listen a words by music or else. I pray to have normal hearing in someday.

John Micknowicz said at October 11, 2010 6:43 PM:

My wife is a very young and pretty 54 year old who was diagnosed quite suddenly (about) 6 years ago with Ushers syndrome. This, as you know takes away vision and hearing. She has very limited central vision only and became totally deaf in right ear about 2 years ago. Last week she lost total hearing in her other ear and cannot even hear her own voice or control the volume of it. We have no family nearby and never had many friends. very few stick by you when you are no longer any fun. PLEASE help .... we will do anything. Our lives are virtually over at this point anyway. Please consider her for your testing purposes whatever the cost. We have an appt with dr tomorrow to inject steroids to the inner ear as a last resort B4 cochlear implant. Neither of us have any knowledge of braille or sign language.PLEASE contact me....I am begging you !!
John

Anonymous said at March 8, 2011 3:26 PM:

My ENT said that it is a miracle that I can hear low voices without my hearing aid.
I have been drinking 2 cups of fresh carrot juice that I made myself on the juice extractor machine.
If anyone see this comment please contact University of Michigan who is having a research about this subject.
You can contact me directly at tonybakerian@yahoo.com. I might have accidently discovered something.

Angelo Carlini said at July 26, 2012 8:31 PM:

Fascinated by this concept of gene therapy. My hearing diminished when I worked at a mechanical machine shop which employed a "punch press" to produce thousands of aluminum rings. Though not realized at the time, the constant repetition of that punch press (its loud noise as it operated) was thought to have been the source of my hearing loss. I have worn cheap digital hearing aids as of late but, they don't really do it like natural. I would willingly volunteer as a "guinea pig" if it could ultimately help me and others. Please keep me current of this gene therapy concept.

Don Meadows said at April 27, 2013 2:42 AM:

Any further progress with this procedure. The report was dated 2003. In the report it mentioned....."within 10 or at most 20 years........will be a curable disorder." Any further updates on this procedure?

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