Dr. Kelley is chief of the Laboratory of Cochlear Development and the Section on Developmental Neuroscience at the National Institute on Deafness and Other Communication Disorders, as well as a senior investigator there, and an adjunct associate professor in the department of biology at the University of Maryland in College Park.
The loss of cochlear mechanosensory hair cells is the primary cause of acquired hearing impairment. In contrast with the situation for all other vertebrates, mammals' hair cells are not regenerated after they are lost. As a result, traumas that lead to hair cell loss cause permanent hearing deficits. The use of hearing aids or cochlear implants can significantly mitigate these losses, but they don't constitute a cure. The regeneration of hair cells, on the other hand, has the potential for permanent recovery.
Activation of a well-conserved signaling molecule, called Notch, has been shown to prevent hair cell formation. In embryos, Notch signaling plays an important role in ensuring that only the correct number of hair cells form, but, in adults, it had been suggested that continued or renewed activation of this pathway, particularly following hair cell damage, might play a role in preventing new hair cells from forming.
Recent research from the laboratory of Albert Edge, PhD, in the Tillotson Unit of the Eaton-Peabody Laboratory at Massachusetts Eye and Ear Infirmary, directly tested this hypothesis by taking advantage of a newly-generated drug designed to prevent activation of Notch through inhibition of the enzyme γ-secretase. In the new study, which was published in Neuron (2013;77:58), young mice were deafened by exposure to loud noise and then given the γ-secretase inhibitor in just one ear. Within a few days of application, changes consistent with inhibition of Notch signaling were observed in the drug-treated ear, and, after three months, anatomic and physiologic assessments indicated some recovery of cochlear function. Again, recovery only occurred in the drug-treated ear.
While the recovery was modest in terms of overall ability to hear, improvements in hearing thresholds were correlated with regions of the cochlea with the highest number of new hair cells. Moreover, the authors used several genetic mouse models to provide evidence that the new hair cells were truly new and not the result of protection or recovery of existing cells. The same mouse models allowed them to determine that the new hair cells arose from surrounding cochlear supporting cells.
This study represents several important advances in the potential development of clinical therapies aimed at regenerating hair cells and restoring hearing in humans. First and foremost, this is one of only a handful of studies in which auditory or vestibular function has been improved in a mammal following hair cell damage. Second, this is the first such study in which improvement was achieved using a pharmacological approach, which has the potential for clinical development. Finally, the fact that the role of Notch was initially demonstrated through basic biological research reinforces the validity of current strategies.
As is the case with all scientific studies, there are important caveats to consider as well. The overall level of functional recovery in these animals was small, and the parameters of the study were not necessarily consistent with the most prevalent type of human hair cell loss—gradual decrease over decades in an aging adult. Also, while Notch is a primary target of γ-secretase, it is not the only molecule activated by this enzyme, suggesting the possibility that Notch is not the crucial factor responsible for the observed recovery. But, as a first step, the demonstration that a drug treatment can be used to induce the regeneration of some hair cells through the modulation of a developmental program is certainly something to be excited about.