The Potential And Limitations Of Gene Therapy For Hearing Loss
Regenerating sensory hair cells, which produce electrical signals in response to vibrations within the inner ear, could form the basis for treating age- or trauma-related hearing loss. One way to do this could be with gene therapy that drives new sensory hair cells to grow.
Researchers at Emory University School of Medicine have shown that introducing a gene called Atoh1 into the cochleae of young mice can induce the formation of extra sensory hair cells.
Their results show the potential of a gene therapy approach, but also demonstrate its current limitations. The extra hair cells produce electrical signals like normal hair cells and connect with neurons. However, after the mice are two weeks old, which is before puberty, inducing Atoh1 has little effect. This suggests that an analogous treatment in adult humans would also not be effective by itself.
The findings were published in the Journal of Neuroscience.
“We’ve shown that hair cell regeneration is possible in principle,” says Ping Chen, PhD, associate professor of cell biology at Emory University School of Medicine. “In this paper, we have identified which cells are capable of becoming hair cells under the influence of Atoh1, and we show that there are strong age-dependent limitations on the effects of Atoh1 by itself.”
The first author of the paper, Michael Kelly, now a postdoctoral fellow at the National Institute on Deafness and Other Communication Disorders, was a graduate student in Emory’s Neuroscience program.
Kelly and his coworkers engineered mice to turn on the Atoh1 gene in the inner ear in response to the antibiotic doxycycline. Previous experimenters had used a virus to introduce Atoh1 into the cochleae of animals. This approach resembles gene therapy, but has the disadvantage of being slightly different each time, Chen says. In contrast, the mice have the Atoh1 gene turned on in specific cells along the lining of the inner ear, called the cochlear epithelium, but only when fed doxycycline.
Young mice given doxycycline for two days had extra sensory hair cells, in parts of the cochlea where developing hair cells usually appear, and also additional locations.
The extra hair cells could generate electrical signals, although those signals weren’t as strong as mature hair cells. Also, the extra hair cells appeared to attract neuronal fibers, which suggests that those signals could connect to the rest of the nervous system.
“They can generate electrical signals, but we don’t know if they can really function in the context of hearing.” Chen says. “For that to happen, the hair cells’ signals need to be coordinated and integrated.”
Although doxycycline could turn on Atoh1 all over the surface of the cochlea, extra sensory hair cells did not appear everywhere. When they removed cochleae from the mice and grew them in culture dishes, her team was able to provoke even more hair cells to grow when they added a drug that inhibits the Notch pathway.
Manipulating the Notch pathway affects several aspects of embryonic development and in some contexts appears to cause cancer, so the approach needs to be refined further. Chen says that it may be possible to unlock the age-related limits on hair cell regeneration by supplying additional genes or drugs in combination with Atoh1, and the results with the Notch drug provide an example.
“Our future goals are to develop approaches to stimulate hair cell formation in older animals, and to examine functional recovery after Atoh1 induction,” she says.
Sources: http://feedproxy.google.com/~r/mnt/healthnews/~3/zlMTYQphCEI/245329.php
Tinnitus Key Cellular Mechanisms Identified
About 10% of the population is affected by hearing loss and tinnitus, a perception of sounds, such as ringing or buzzing in the ear in the absence of corresponding external sound, which typically develops after acoustic over-exposure to loud noises. Scientists have speculated that tinnitus is caused by damaged nerve cells within the ear, but so far, there are no drugs available for the treatment or prevention of the condition.
The journal Hearing Research now reveals that researchers from the University of Leicester’s Department of Cell Physiology and Pharmacology have discovered a cellular mechanism, which could be responsible for the development of tinnitus after exposure to loud noises. The finding could pave the way for the development of new drugs to treat tinnitus, and researchers are currently investigating potential drugs that could prevent the condition.
Research leader, Dr. Martine Hamann from Leicester University explained:
“We need to know the implications of acoustic over exposure, not only in terms of hearing loss but also what’s happening in the brain and central nervous system. It’s believed that tinnitus results from changes in excitability in cells in the brain – cells become more reactive, in this case more reactive to an unknown sound.”
The researchers examined cells in the brain’s dorsal cochlear nucleus area, which carries acoustic signals from the ear’s nerve cells into the parts of the brain that decode and ‘interpret’ sounds. Exposure to loud noises affects some of the neurons in the dorsal cochlear nucleus to behave in an uncontrolled manner by starting to fire erratically, which ultimately leads to tinnitus.
Dr Hamann declared:
“We showed that exposure to loud sound triggers hearing loss a few days after the exposure to the sound. It also triggers this uncontrolled activity in the neurons of the dorsal cochlear nucleus. This is all happening very quickly, in a matter of days.”
A major breakthrough was the team’s discovery of the particular cellular mechanism that leads to the neurons’ over-activity. They discovered that if potassium channels that help to control the nerve cell’s electrical activity malfunction, the neurons are unable to return to a balanced resting state. These cells normally fire regularly and also regularly return to a resting state, yet if the potassium channels are malfunctioning, the cells are unable to return to a resting state and therefore continuously fire in random bursts, which creates the sensation of a constant noise even though there is no noise.
Dr Hamann explained:
“In normal conditions the channel helps to drag down the cellular electrical activity to its resting state and this allows the cell to function with a regular pattern. After exposure to loud sound, the channel is functioning less and therefore the cell is constantly active, being unable to reach its resting state and displaying those irregular bursts.”
Even though numerous scientists have explored the dynamics of why tinnitus occurs, this is the first time that researchers have managed to characterize the cellular bursting activity in association with specific potassium channels. The ability to identify the potassium channels in the early stages of tinnitus paves the way for the development of new potential drug treatments to prevent the condition.
At present, Dr Hamann’s team is exploring potential drugs that can control the damaged cells so that their erratic firing is blocked and they can revert to a resting state. The discovery of suitable drug components would mean that patients would be protected against the onset of tinnitus after experiencing acoustic overload. However, the development of a suitable drug to prevent tinnitus will take some years, given that investigations are still in their preliminary stage.
Leicester University, in collaboration with Autifony Therapeutics Ltd, will continue to conduct further pharmaceutical research via a Medical Research Council Case studentship, which is set to commence in October 2012.
Vivienne Michael, Chief Executive of Deafness Research UK, concluded:
“We’re pleased to hear about this progress in such a debilitating hearing impairment. The charity continues to fund research into better treatments for tinnitus, with the ultimate aim of a cure. Our free information leaflets offer immediate help to sufferers and our national helpline provides additional support. Regularly tinnitus generates the most requests for help.”
Written by Petra Rattue
Sources: http://feedproxy.google.com/~r/mnt/healthnews/~3/LpiqK_ULV1I/245357.php
A cure for tinnitus? Hope for millions tormented by ringing in ears as scientists edge closer to developing first drug treatments
The first drug treatments to prevent the onset of tinnitus could soon be developed after doctors discovered how to tone down overactive neurons in the brain.
Researchers from the University Of Leicester have identified a key cellular mechanism that could underlie the development of ringing in the ears following exposure to loud noises.
The discovery could lead to novel
tinnitus treatments, and investigations into potential drugs to prevent
tinnitus are underway.
Preventable? The first drug treatments to stop the onset of tinnitus could be developed after doctors found how to tone down overactive neurons in the brain
Around five million Britons suffer
with tinnitus at some point in their lives. The condition causes the
patient to hear a sound that has no obvious source.
Although the word tinnitus comes from
the Latin for ‘ringing’, the noise can be a buzz, hum or even a whistle – heard in one ear, both ears or in the middle of the head.
For most people the problem is mild, or disappears with time. But for others it can become chronic and almost intolerable.
There are currently no drugs available to treat or prevent tinnitus.
Scientists have previously speculated that it results from damage to nerve cells connected to the ears.
Lead researcher Dr Martine Hamann said: ‘We need to know the implications of acoustic over-exposure, not only in terms of hearing loss but also what’s happening in the brain and central nervous system.
‘It’s believed that tinnitus results from changes in excitability in cells in the brain – cells become more reactive, in this case more reactive to an unknown sound.’
Dr Hamann and her team looked at cells in an area of the brain called the dorsal cochlear nucleus – the relay carrying signals from nerve cells in the ear to the parts of the brain that decode and make sense of sounds.
Following exposure to loud noises, some of the nerve cells in the dorsal cochlear nucleus start to fire erratically, and this uncontrolled activity eventually leads to tinnitus.
Around five million Britons suffer with tinnitus at some point in their lives. The condition causes the patient to hear a sound that has no obvious source
Dr Hamann said: ‘We showed that
exposure to loud sound triggers hearing loss a few days after the
exposure to the sound. It also triggers this uncontrolled activity in
the neurons of the dorsal cochlear nucleus.
‘This is all happening very quickly, in a matter of days.’
In a key breakthrough, the team also discovered the specific cellular mechanism that leads to the neurons’ over-activity.
Malfunctions in specific potassium channels that help regulate the nerve cell’s electrical activity mean the neurons cannot return to an equilibrium resting state.
Ordinarily, these cells only fire regularly and therefore regularly return to a rest state.
However, if the potassium channels are not working properly, the cells cannot return to a rest state and instead fire continuously in random bursts, creating the sensation of constant noise when none exists.
Dr Hamann said: ‘In normal conditions the channel helps to drag down the cellular electrical activity to its resting state and this allows the cell to function with a regular pattern.
‘After exposure to loud sound, the channel is functioning less and therefore the cell is constantly active, being unable to reach its resting state and displaying those irregular bursts.’
Although many researchers have investigated the mechanisms underlying tinnitus, this is the first time that cellular bursting activity has been characterised and linked to specific potassium channels.
Identifying the potassium channels involved in the early stages of tinnitus opens up new possibilities for preventing tinnitus with early drug treatments.
Dr Hamann’s team is currently investigating potential drugs that could regulate the damaged cells, preventing their erratic firing and returning them to a resting state.
If suitable drug compounds are discovered, they could be given to patients who have been exposed to loud noises to protect them against the onset of tinnitus.
These investigations are still in the preliminary stages, and any drug treatment would still be years away.
The research was published in the journal Hearing Research.
It was funded by a Research Councils UK fellowship to Dr Hamann, a grant from the Wellcome Trust and a PhD studentship from GlaxoSmithKline, with follow-up investigations funded by a three-month grant from Deafness Research UK.
Study Identifies Key Cellular Mechanisms Behind The Onset Of Tinnitus
Researchers in the University of Leicester’s Department of Cell Physiology and Pharmacology have identified a cellular mechanism that could underlie the development of tinnitus following exposure to loud noises. The discovery could lead to novel tinnitus treatments, and investigations into potential drugs to prevent tinnitus are currently underway.
Tinnitus is a sensation of phantom sounds, usually ringing or buzzing, heard in the ears when no external noise is present. It commonly develops after exposure to loud noises (acoustic over-exposure), and scientists have speculated that it results from damage to nerve cells connected to the ears.
Although hearing loss and tinnitus affect around ten percent of the population, there are currently no drugs available to treat or prevent tinnitus.
University of Leicester researcher Dr Martine Hamann, who led the study published in the journal Hearing Research, said: “We need to know the implications of acoustic over exposure, not only in terms of hearing loss but also what’s happening in the brain and central nervous system. It’s believed that tinnitus results from changes in excitability in cells in the brain – cells become more reactive, in this case more reactive to an unknown sound.”
Dr Hamann and her team, including PhD student Nadia Pilati, looked at cells in an area of the brain called the dorsal cochlear nucleus – the relay carrying signals from nerve cells in the ear to the parts of the brain that decode and make sense of sounds. Following exposure to loud noises, some of the nerve cells (neurons) in the dorsal cochlear nucleus start to fire erratically, and this uncontrolled activity eventually leads to tinnitus.
Dr Hamann said “We showed that exposure to loud sound triggers hearing loss a few days after the exposure to the sound. It also triggers this uncontrolled activity in the neurons of the dorsal cochlear nucleus. This is all happening very quickly, in a matter of days”
In a key breakthrough in collaboration with GSK who sponsored Dr Pilati’s PhD, the team also discovered the specific cellular mechanism that leads to the neurons’ over-activity. Malfunctions in specific potassium channels that help regulate the nerve cell’s electrical activity mean the neurons cannot return to an equilibrium resting state.
Ordinarily, these cells only fire regularly and therefore regularly return to a rest state. However, if the potassium channels are not working properly, the cells cannot return to a rest state and instead fire continuously in random bursts, creating the sensation of constant noise when none exists.
Dr Hamann explained: “In normal conditions the channel helps to drag down the cellular electrical activity to its resting state and this allows the cell to function with a regular pattern. After exposure to loud sound, the channel is functioning less and therefore the cell is constantly active, being unable to reach its resting state and displaying those irregular bursts.”
Although many researchers have investigated the mechanisms underlying tinnitus, this is the first time that cellular bursting activity has been characterised and linked to specific potassium channels. Identifying the potassium channels involved in the early stages of tinnitus opens up new possibilities for preventing tinnitus with early drug treatments.
Dr Hamann’s team is currently investigating potential drugs that could regulate the damaged cells, preventing their erratic firing and returning them to a resting state. If suitable drug compounds are discovered, they could be given to patients who have been exposed to loud noises to protect them against the onset of tinnitus.
These investigations are still in the preliminary stages, and any drug treatment would still be years away.
Sources: http://feedproxy.google.com/~r/mnt/healthnews/~3/6_mHMOLcQPk/245282.php