January 10, 2013
(The New York Times News Service) -- Boston researchers have for the first time used a drug to regenerate the delicate hair cells that sense sound in the ears of adult mice, in a promising initial step toward a potential treatment for hearing loss.
Hair cells damaged by loud noises or lost during aging don't regrow in people, but in the mouse experiments published on Wednesday, the scientists coaxed new cells to develop, enabling the animals to recover modest hearing.
The deaf mice were far from cured; the improvement in hearing was much less than could be achieved by an existing technology, called a cochlear implant. But researchers not involved in the work said the results, published in the journal Neuron, were important because they showed such regeneration was possible and suggested a similar nonsurgical approach could one day be tested in people.
"What's really novel is that they showed you can use a pharmacological agent, basically a drug, to get some level of hearing recovery in animals in which they've lost their hearing because of exposure to loud noise," said Matthew Kelley, chief of the laboratory of cochlear development at the National Institute on Deafness and Other Communication Disorders.
The study also highlights the serendipity of biomedical research and drug development; the medication the researchers used was originally developed as a possible Alzheimer's drug.
The quest to regrow hair cells began in the 1980s, when it first became clear that lower animals, such as birds and fish, can regenerate these cells, which have hair-like structures, but are sensory cells. Some previous efforts using gene therapy succeeded in mammals, but they were technically difficult or more invasive, and there has been skepticism about whether hair cells were truly new in some studies.
Albert Edge, a scientist at the Massachusetts Eye and Ear Infirmary and Harvard Medical School, set out to use an approach that could unequivocally tell scientists the origins of hair cells. He built on years of research that revealed which signals guide stem cells to develop into hair cells.
Scientists had learned that during development, a cell signaling system called Notch was important in determining whether a cell developed into a hair cell or not. Notch signaling caused a type of stem cells, which are naturally found in the ear and are called supporting cells, not to develop into hair cells.
Edge wanted to use a drug to turn off that signal. Fortunately, he knew of a class of experimental Alzheimer's drugs called gamma-secretase inhibitors, which many pharmaceutical companies had developed over the last few years. One of the problems with the drugs for treating dementia had been their lack of specificity. In addition to interfering with the formation of the protein that is found in clumps in the brains of Alzheimer's patients, it stopped Notch and caused side effects. But that lack of specificity presented an opportunity for Edge.
Edge obtained a handful of drugs made by various companies and tried them out on cells in a dish to see which ones worked best. A drug called LY411575, developed by the pharmaceutical giant Eli Lilly and Co., turned out to be the most potent.
To avoid side effects caused by administering the drug systemically, the researchers tried delivering the drug locally, to the ear of the mouse. A comparable way of delivering a drug if it were being given to a person, Edge said, would be to inject the drug into a part of the ear.
A month after the mice were treated, the researchers found that supporting cells in the mouse ears had turned into new hair cells. The new cells weren't evenly distributed; they grew in the part of the ear that detected lower pitches. In some ways that unevenness was a disappointment, but it was also a perfect test: the recovery in hearing was in the frequency range that the scientists would have predicted based on the location of the cells.
To determine whether the hair cells were formed from the supporting cells and truly new, the researchers used genetic manipulation to fluorescently tag the ears' supporting cells. Hair cells that developed from supporting cells also glowed, showing they weren't merely damaged hair cells that were recovering. Outside researchers praised that step, which showed unambiguously which cells were new.
Researchers were quick to add that much remains to be done to see how broadly such a technique could be used in people. The mice were deafened by acute exposure to loud noise, which is different than the hearing loss during normal aging, which has a variety of causes. Because cochlear implants are fairly successful, the technique would also have to be improved and do a better job before it would make sense as a treatment.
Edge said that the animals would still be considered quite hard of hearing after treatment; they can hear only very loud noises. He hopes to see whether there might be other drugs or ways to trigger a greater improvement in hearing.
"It's a first step. It needs to be tweaked and improved, but for people who have almost no hearing to get some back" would be great, said Yehoash Raphael, a professor of otolaryngology at the University of Michigan, who was not involved in the work. Ultimately, he thinks, such an approach "is probably going to work better than a cochlear implant, which is the solution now, and will improve hearing perceptibly and probably be a blessing for a large number of patients."
A spokeswoman for Eli Lilly said the drug the researchers used had never advanced into clinical development, and the company is not investigating any drugs for hearing loss. The company does not have any gamma-secretase inhibitors among its portfolio of 60 investigational medicines, and Edge has no financial ties to the company.
Copyright 2013 The New York Times News Service. All rights reserved.