In addition to the below post on gene therapy, keep a watch out for a review paper on the topic (by yours truly) that was just accepted into Hearing Research.

Deafness and hearing impairment are serious medical concerns in America, with nearly 30 million Americans affected to some degree. This is such a widespread problem in our society due to the combined effects of loud noises, aging, and heredity. Hearing loss happens when cochlear hair cells are lost (for a primer on the cochlea and hair cells, go here). Mammals, including humans, are unable to re-grow hair cells although birds and a few other species can. This is one reason I am so fascinated by birds---you can deafen them repeatedly, and within 2 weeks, they regenerate hair cells and their hearing is restored! If people could also do this, no one would ever suffer from deafness ever again. This aim, the regeneration of hair cells in humans, is the focus of my lab and my thesis. (continued......)

In order to sum up a very large body of research stemming from our lab, I'm going to talk about a Nature Medicine paper from 2005 which was the realization of a lot of our theories.

The idea goes like this: a certain gene, called Atoh1, is solely expressed in hair cells during their development and differentiation. It is necessary and sufficient for hair cell development, and in Atoh1-knockout mice, no hair cells are seen. This convinced us that Atoh1 was an excellent candidate for viral over-expression, possibly resulting in new hair cells in the deaf ear.

Viral over-expression refers to the ability to insert a gene of interest into an inactivated virus. The virus is no longer harmful, and no longer replicates its DNA when it infects a cell. Instead it replicated the gene of interest, forcing the cell to express that protein. Our lab used a type of virus called an adenovirus, and inserted Atoh1 under the control of the promiscuous human-CMV promoter. The next step was to inject the modified virus into the fluids of the deaf inner ear, and observe whether hair cells regenerated as a result.

To deafen an animal, we use a combination of the antibiotic kanamycin and the diuretic ethacrynic acid. These two drugs, when administered in close succession, result in the death of all hair cells in the cochlea. Five days following the deafening procedure, we administered a very small volume of the modified virus into the scala media, the area where the hair cells lie. Then, we waited. During the interim, we tested the animals' hearing thresholds ever few weeks with Auditory Brainstem Response (ABR) measurement. With this technique, we can measure the activity in the brain while an animal is perceiving a sound of a controlled intensity. In this way, we can "step down" in the decibel level of the presented sound, and when the ABR gets no response, we can infer that that is the level of the animal's hearing threshold.

Here is a scanning electron micrograph of a normal hair cell region (called the organ of Corti):

And here is what the same region looks like after all the hair cells are eliminated (deafened):

It is immediately obvious that the ordered structure of the previous picture has completely changed. The "V" shaped structures are the "hairs" of the hair cells. These are called stereocilia, and they project into the fluid space to receive vibrations when sound waves pass through.

So, what were the results of our study? Not only did we find a significant amount of regenerated hair cells in the virus-treated ears, but their hearing was significantly improved as well. As a control on all animals, only the left cochlea received the virus, the right cochlea received nothing. There was a large difference in hearing between the left and right ears of the guinea pigs (left was better). I will explain the figure below in some detail:

A-C: SEMs of virus-treated organ of Corti 2 months post treatment. Many hair cells have regenerated and the organization is in rows, like normal. Some hair cells are ectopic. These are three representative levels of recovery with A being the best and C being the worst. Even C has a significant level of regeneration.
D. This is an organ of Corti which was deafened and received no treatment (a right ear). There are no hair cells.
E. This cochlea received a sham virus surgery. Instead of Atoh1, there was no gene insert in the virus. No regeneration was seen.
F. This is a higher magnification of an inner hair cell.
G. This is a higher magnification of an outer hair cell.

It is clear that there is an increase in hair cells after Atoh1 virus therapy, and no hair cell regeneration in controls. In addition we also observed some improvements in ABR thresholds 2 months after the virus therapy (below). In the figure below, A represents a "hearing waveform" of the treated ear corresponding to a threshold of about 60 decibels, while on the right, B represents a "deaf waveform" of the control ear, with no response even at 105 decibels.

We concluded that virally-mediated overexpression of Atoh1 in the deaf ear resulted in numerous hair cells as well as hearing improvement after 2 months. This therapy is still in its infancy and very far away from being developed for humans

Reference: Izumikawa et al. 2005. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nature Medicine. 11, 3, pg 271-276.