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Gene Therapy Reportedly Restores Hearing in Mammals
Ann Arbor, Mich — Researchers from the University of Michigan (U-M) Medical School have inserted a corrective gene using a virus and restored the cochlear hair cells in adult guinea pigs—reportedly the first restoration of auditory hair cells at the structural and functional levels in mature living mammals—according to a study published in Nature Medicine (February 13 edition). The researchers later demonstrated that the animals responded to sounds.

Yehoash Raphael, PhD

After 11 years of intensive research, the U-M researchers succeeded in using gene therapy to grow new auditory hair cells and restore hearing in deafened adult guinea pigs—a major achievement in the search for new ways to treat hearing loss in humans. Guinea pigs are used in hearing research, because their ears are large and their inner ear structure is virtually identical to that of humans. For years, scientists have been searching for a way to regenerate functioning hair cells. (For a recent update on hair cell regeneration, restoration, and otoprevention, see the article by Edwin Rubel, PhD, and his comments in the October 2004 HR, pgs 18-20, 62).

Yehoash Raphael, PhD, an associate professor of otolaryngology at U-M’s Kresge Hearing Research Institute, who directed the U-M study, credits advances made by other scientists worldwide for his team’s success. “Progress in gene delivery methods and in understanding of the molecular mechanism that controls hair cell development facilitated the experimental approach used by our group,” says Raphael.

“We inserted a gene called Atoh1, a key regulator of auditory hair cell development, into non-sensory epithelial cells that remain in the deafened inner ears of adult guinea pigs, whose original hair cells were destroyed by exposure to ototoxic drugs,” Raphael explains. “Eight weeks after treatment, we found new auditory hair cells in the Atoh1-treated ears of the research animals. Auditory tests indicated that the generation of new hair cells coincided with restoration of hearing thresholds.”

Raphael describes Atoh1 (formerly known as Math1) as a “pro-hair cell gene” which normally is active only during embryonic development. Originally discovered in fruit flies, the genis is present in all animals, including humans. During the embryonic stage of animal development, Atoh1 is turned on, or expressed, in inner ear cells destined to become hair cells, while its expression is inhibited in supporting (non-sensory) cells.

“Our goal was to find a way to activate Atoh1 in mature non-sensory cells in the inner ear, causing them to develop into new hair cells,” says Raphael.

Masahiko Izumikawa, MD

The first author of the paper, Masahiko Izumikawa, MD, is a research fellow from Kansai Medical University in Osaka, Japan, who is now training with Raphael at the U-M Medical School. Izumikawa used an adenoviral vector to deliver the Atoh1 gene to inner ear cells. He injected the Atoh1 vector into the left ears of 10 guinea pigs that had received large doses of ototoxic drugs 4 days earlier to destroy their hair cells. The same procedure, but without transfer of the Atoh1 gene, was performed on matched control animals. The right ears of the deafened animals did not receive the Atoh1 treatment and served as an additional control.

Microscopic images of inner ears from deafened animals taken 3 days after ototoxic drug treatment confirmed that the drugs had destroyed all the hair cells. However, images of inner ears treated with Atoh1, taken 8 weeks after inoculation, showed large numbers of hair cells in the cochlea. Images of control ears treated with the vector alone, or with the vector in combination with green fluorescent protein, showed no hair cells. Contralateral (right, untreated) ears were also devoid of hair cells.

“Because we eliminated all the original hair cells in the organ of Corti, we know that any new hair cells must have developed from non-sensory cells, which were induced by Atoh1 gene expression to change into auditory hair cells,” says Izumikawa.

To find out whether the new hair cells were actually functional, the scientists used auditory brainstem response (ABR) tests. “Four weeks after treatment, the threshold levels indicated profound deafness. But at 8 weeks, average thresholds in Atoh1-treated ears were lower (better) at all frequencies than in the control ears. This is the most exciting finding of our study,” says Raphael, who adds that he repeated the tests four times to be sure of his results.

Restoring auditory threshold levels is an important advance, but Raphael cautions that it shouldn’t be considered the same as restoring normal hearing. “At this early stage, the structural and functional repairs are incomplete and the hearing of these animals is likely to be distorted,” he says. “For this and other reasons, it will be several years before Atoh1 gene therapy is ready for human testing.”

In future research, Raphael plans to test Atoh1 treatment in aged animals and animals deafened by noise exposure, rather than drugs. He also wants to determine if the treatment is effective months or years after the original hair cells have degenerated.

Previous research by Raphael and his U-M team, published in the June 1, 2003 issue of the Journal of Neuroscience, demonstrated it was possible to grow new hair cells in non-deafened guinea pigs by inserting Atoh1 into non-sensory epithelial cells lining the inner ear.

Additional study collaborators and co-authors included Ryosei Minoda, MD, and Kohei Kawamoto, MD, former U-M research fellows; Karen A. Abrashkin, former U-M undergraduate student; Donald L. Swiderski, PhD, research associate; and David F. Dolan, PhD, U-M research associate professor. The research was supported by the National Institute on Deafness and Other Communication Disorders (NIDCD) of the National Institutes of Health, a gift from Berte and Alan Hirschfield, Center for Hearing Disorders, and GenVec Inc, a biopharmaceutical company in Gaithersburg, Md. GenVec provided its proprietary adenovector with the Atoh1 gene insert. Douglas E. Brough, a co-author of the paper, is a GenVec employee. The university reports that Raphael has no financial interest in the company.

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Starkey Opens SHRC Research Center in Berkeley, Calif
Berkeley, Calif – Starkey Laboratories has opened its new Starkey Hearing Research Center (SHRC) in Berkeley, Calif. The SHRC, a division of Starkey’s Hearing Research and Technology department, is reported to solidify Starkey’s long-term commitment to developing advanced hearing instrument technology.

Areas of research at the SHRC will include auditory science, digital signal processing, wireless applications, directional technology, diagnostic procedures and validation techniques.

Long-time hearing instrument researcher Brent Edwards, PhD, has been appointed SHRC Executive Director. “We are excited about this challenging opportunity and to be a part of the Starkey family,” says Edwards. “We look forward to applying the science of hearing to solutions for the hearing impaired. Today’s technologies offer us unique opportunities to continue Starkey’s history of innovation.”

The SHRC is located two blocks from the University of California, Berkeley campus and is near Stanford University, the University of California, San Francisco and several other major universities.

The Center will collaborate with these and other universities to investigate new areas of benefit for the hearing impaired. SHRC researchers will also work closely with colleagues at the company’s headquarters in Eden Prairie, Minn, to translate research results into new products offered by Starkey.

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Hearing Components & GN ReSound Develop New Aid
Oakdale, Minn — Hearing Components announced a new technology alliance with GN Resound, Bloomington, Minn, to make a compliant mini-canal hearing aids designed for demonstration and loaning to hearing aid users. The licensing arrangement allows GN Resound to create what the company describes as the first practical instant-fitting, final-electronic-product-comparable demonstrator and loaner completely-in-the-canal (CIC) hearing aids.

Hearing Components’ Comply™ Capsule System utilizes viscoelastic foam with a specially designed capsule that features a built-in patented compliant coupling technology. The mini-canal sized capsule is designed to hold the electronic parts necessary to build multi-channel digital aids. GN Resound utilizes this system with their electronics and software to create their own demonstration instrument for hearing professionals.

Digital electronic technology enables customization of circuits in much smaller instruments and allows for adjustments for each individual’s hearing loss using standard methods and software. The patient information—which is already stored electronically in the hearing professional’s office—can be directly downloaded into the electronic capsule in seconds making for a demonstration model that allows the patient to experience the true electronics without an impression or custom fitting. When the electronics are combined with the Comply Capsule and Snap Tips, this system offers patients the first digital custom demonstration, according to the company.

“The combination of the Hearing Components and GN Resound technologies provides the practitioner with a superior solution for their patients who want to experience how a custom aid performs,” says Hearing Components National Sales Manager Karen Dee. “The technology alliance has created a significant win-win opportunity for practitioners and their patients. Also, when a patient who wears a custom aid must surrender it for factory service or repair, the dispensing professional can relieve this hardship by offering a temporary, yet customized, loaner to the patient.”

For more information, contact Hearing Components at (800) 872-8986 or visit www.hearingcomponents.com.

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Cell Phones Hit 2 Billion Mark in ‘05; Implications for Hearing Aids
In its Technology, Media & Telecommunications (TMT) Trends: Predictions 2005, the consulting firm Deloitte & Touche (www.deloitte.com) predicts that the global wireless phone market will grow to 2 billion subscribers by the end of 2005. The firm also predicts that:

• Voice will continue to be the primary source of cellular mobile revenues (80%), although a significant minority of voice customers will take a second 2G subscription for data, creating mobile penetration surpassing 100% in some markets.

• Dozens of 3G networks will go live in 2005. In the 2G and 3G cell phone platforms, messaging will continue to be the primary source of non-voice use.

• Chat, instant messaging, and other emerging services will grow substantially. So will the lucrative mobile content market. For example, cell phone ring tones are already a $2 billion industry (about half the size of the US retail hearing aid market).

Deloitte & Touche say that the impact of radio frequency identification devices (RFID)—which use wireless technology to transmit product serial numbers and other information from tags to scanning devices without human intervention—are “expected to be enormous, immediate, and global, with literally billions of RFID tags being deployed in 2005.” The firm states that RFID will initially be based on closed-loop, proprietary networks, but will eventually spill out onto public networks, creating a huge amount of data traffic.

The above trends may be of great future consequence for the hearing industry and professional and consumer groups who are trying to keep hearing aid compatibility (HAC) issues in the forefront of the FCC’s agenda. The giant telecommunications industry has been reluctant to address HAC concerns (see HR News, January 2004, p 10). Additionally, the trends may verify many industry experts’ predictions that “total communication devices” will evolve and ultimately link everyday items like cell phones, computers, stereos, etc, to hearing instruments.

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Congressional Support for Tax Hearing Aid Tax Credit Grows
Washington, DC — As reported in last month’s edition of HR, Congressional Representative Jim Ryun (R-KS) reintroduced the Hearing Aid Tax Credit Assistance Act (HR 414) on January 26th, and he has been joined by 20 co-sponsors. Momentum for HR 414 is growing, and by mid-February, there were already a total of 32 co-sponsors, with 12 new Congressional Representatives signing on.

The reintroduced bill is identical to last session’s HR 3103, also authored by Congressman Ryun, and would provide $500 ($1000 for binaural fittings) towards the purchase of a hearing aid, once every 5 years, for individuals under the age of 18 or for those age 55 and older, or those purchasing a hearing aid for someone under 18.

An informal “Hearing Aid Tax Credit Coalition”—which is composed of the Hearing Industries Assn (HIA), American Academy of Audiology (AAA), American Speech-Language Hearing Assn (ASHA), International Hearing Society (IHS), Deaf and Hard of Hearing Alliance (DHHA), and Self Help for Hard of Hearing People (SHHH)—has been actively setting up meetings with both Senate and House offices to gain support for the new bill. Currently, the coalition’s main focus has been gaining Senate support for the issue as Senator Norm Coleman (R-MN) prepares to reintroduce a companion bill later this spring.

The allied organizations will call on their membership to contact Senators via email, fax, and phone, urging the Congressmen to become cosponsors to Senator Coleman’s bill. Passage of the tax credit legislation is also the key focus of the HIA’s “Hearing on the Hill” event on May 17-18, 2005 which coincides with Better Hearing and Speech Month.

For more information on the Hearing Aid Assistance Tax Credit Act, see the Dec 2003 HR, p 12 and the March 2004 HR, p 8.

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AAAS Conference Focuses on Hair Cell Restoration
Rockville, Md — Research on ways to restore functional hair cells in mammals, including in vivo and in vitro genetic manipulations, application of mitogenic growth factors, and stem cell characterization and transplantation, were presented as part of the Association for the Advancement of Science (AAAS) annual meeting. Sponsored and organized by the American Speech-Language-Hearing Association (ASHA), the symposium also addressed efforts to identify the signaling pathways in the inner ear that are necessary for neuronal survival and regrowth after hair cell loss.

Hair cells are critical for hearing function and are highly susceptible to acoustic trauma, pharmaceutical agents, and microenvironmental changes, such as those associated with aging. The majority of deafness and balance disorders are sensorineural. While it has been known for over 50 years that sensory hair cells can be regenerated in cold-blooded vertebrates, it was not until recently that it was demonstrated that warm-blooded vertebrates, such as mammals, are capable of this process (see p 14). This discovery suggests that hair cell regeneration could be stimulated in humans to cure sensorineural hearing loss, which has long been believed to be irreversible.

Presenters summarized the current state of scientific knowledge about hair cell regeneration and neural regrowth, and identified areas of promise and limitation for future approaches toward treating sensorineural hearing and balance disorders.

Specific presentations included “Hair Cell Regeneration in Non-Mammalian Vertebrates,” by Jennifer Stone, PhD, assistant professor at the University of Washington Medical School and Virginia Merrill Bloedel Hearing Research Institute. Stone reviewed the knowledge base on the spontaneous occurrence of hair cell regeneration in non-mammalian species.

In “Controlling Cell Division During Regeneration of the Mammalian Inner Ear,” Neil Segil, PhD, senior scientist at the House Ear Institute, addressed the effects of hair cell injury in mammals, how the cell cycle can be altered genetically to stimulate the initial stages of hair cell regeneration, and methods for stem cell isolation from the mature cochlea.

Additionally, Steven Green, PhD, associate professor of biological sciences and otolaryngology at the University of Iowa, discussed the challenges associated with promoting neural regeneration and connection to restored hair cells in his presentation, “Control of Spiral Ganglion Neuronal Survival and Axon Growth.”

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Studies Indicate that Diabetes Increases Risk of Hearing Loss
Hearing loss has been added to the list of possible side-effects of diabetes, according to three studies reported on by the Hear-It Web site (www.hear-it.org), and the data suggest that diabetics have a slightly increased risk of hearing impairment. However, the nature of the relationship between diabetes and hearing loss is still unclear.

A study by Vaughan, McDermott, & Fausti entitled “A Large-Scale Study of Auditory Function in Diabetic Veterans” (www.aro.org/archives/2004) involved 694 Americans between the ages of 28 and 85 years. The results indicated that diabetics under the age of 60 have a higher incidence of hearing loss than others in their age group. Diabetes was found to affect the central auditory processing system, resulting in significantly worse hearing. The authors concluded that cochlear test results (OAEs and hearing thresholds) do not reflect significant changes associated with diabetes; auditory changes associated with diabetes occur primarily beyond the cochlea and affect central auditory processing in the form of neural conduction time delays.

An earlier study (“The Effect of Diabetes on Sensorineural Hearing Loss”, Otology & Neurology 2003, No. 3) involving 66,036 people from Maryland indicated that sensorineural hearing loss is more common among diabetics than in the general population. In total, 13% of diabetics suffer from hearing loss, while the same is true for only 10% of non-diabetics.

A study (“Increased Prevalence of Impaired Hearing in Patients With Type 2 Diabetes in Western India, Postgraduate Medical Journal 2000, Vol. 76) of 1,344 people in India found an even greater risk of hearing loss among diabetics. Nearly 1-in-4 people with Type 2 diabetes over the age of 50 used a hearing aid, as compared to just 1-in-14 in the same age group among non-diabetics. The greatest disparity was found among 50-60 year-olds. In this group, diabetics were six times as likely as a non-diabetic to use hearing aids.

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Study Shows Drug and Cognitive Stimulation Slow Alzheimer’s
Richardson, Tex — A program of active cognitive stimulation performed in conjunction with the drug Aricept (donepezil hydrochloride) produces greater mental and functional benefits in patients in the early stages of Alzheimer’s disease than taking the drug alone, according to a study published in the October issue of the Journal of Speech, Language, and Hearing Research. The study was conducted by Texas university researchers and funded by by Eisai Co, Ltd, the Tokyo-based pharmaceutical company that manufactures Aricept, and Pfizer, Inc, of New York, the US distributor of the drug.

The results add to the mounting evidence that active cognitive stimulation may slow the rate of verbal and functional decline and decrease negative emotional symptoms in Alzheimer’s patients when combined with an acetylcholinesterase inhibitor like Aricept.

Fifty-four patients with mild to moderate Alzheimer’s disease, ranging in age from 54 to 91, took part in the randomized study. Twenty-eight of the patients received Aricept only, while 26 were given the drug and took part in a cognitive stimulation program consisting of 12 hours of intervention treatment by speech-language pathologists over an eight-week period at the beginning of the one-year study. The stimulation program consisted of participant-led discussions requiring homework, reading and discussion on Alzheimer’s treatment and composition of written life stories. Evaluations of the patients were conducted at the end of the fourth, eighth and 12th month.

According to the study, the Aricept-plus-stimulation group showed a slower rate of decline than patients taking Aricept alone. Specifically, benefits include:

• Slower rate of disease progression, as measured by a widely used screening method.
• Reduction in emotional symptoms of irritability and apathy.
• Maintenance of meaningful verbal communication.
• Improvement in patient-reported quality of life.
• Slower decline in functional abilities.

“For decades, attention has been drawn to the brain’s incredible ability to adapt after stroke and traumatic brain injury, ” says Sandra Bond Chapman, PhD, director of the UTD Center for BrainHealth and leader of the study team. “Only recently has the concept called ‘plasticity’ been applied to progressive brain diseases such as Alzheimer’s. The UTD–UT Southwestern study supports the idea that it is possible to stimulate the brain to halt or slow the progression of early-stage Alzheimer’s disease.”

The study was conducted by researchers at the University of Texas at Dallas (UTD) and The University of Texas Southwestern Medical Center at Dallas (UT Southwestern). UTD’s portion of the research was conducted by scientists from the Center for BrainHealth, part of the university’s School of Behavioral and Brain Sciences.

Alzheimer’s is a complex disease that causes the gradual loss of brain cells, making it difficult for those who suffer from it to remember, reason, and use language. Approximately 4.5 million Americans have the disease. Although many things about Alzheimer’s remain a mystery, research continues to yield a better understanding of the disease, more accurate diagnoses and more effective treatments.

The disease is more common in older adults. About one in 10 people over the age of 65 have Alzheimer’s. As many as five in 10 people over the age of 85 have the disease.

The disease was first described in 1906 by German physician Dr. Alois Alzheimer. Although the disease was once considered rare, research has shown that it is the leading cause of dementia.

Besides Chapman, members of the study team included four other researchers, two from UTD (Audette Rackley, MS, and Jennifer Zientz, MS) and two from UT Southwestern (Linda S. Hynan, PhD, Myron F. Weiner, MD).