By Yehoash Raphael, Ph.D.
Recently, it became clear that loud signals can also damage the connecting interface between the hair cell and the auditory nerve. This interface is the synapse. When the synapse is disrupted, hearing is impaired even without the loss of hair cells, leading to a condition called synaptopathy.
Experiments using transgenic mice showed that elevating levels of a specific molecule called NT3 in the area of the synapse can heal synaptopathy caused by exposure to loud noise. Since transgenic technology is a research tool not applicable for clinical use on humans, it is now necessary to design methods for elevating NT3 in human ears, leading to repair of synaptopathy. This is an important task, because if left untreated, synaptopathy progresses to include nerve cell death and permanent hearing deficits.
One potential way to increase NT3 concentration in the cochlea is by the use of gene transfer technology, which is based on infecting cochlear cells with viruses that are engineered to secrete NT3 and not cause infections. A potential risk of this method is that the site of NT3 is not restricted to the area of the synapses affected by the synaptopathy; NT3 can influence other types of cells.
In my lab at the University of Michigan, we tested the outcome of injecting such viruses on the structure and function of normal (intact) ears. We determined that the procedure resulted in the deterioration of hearing thresholds, and the auditory nerve and its connectivity to the hair cells were also negatively affected.
This negative outcome indicates that treatment of synaptopathy should be based on a more specific way to provide NT3 in an area restricted to the synaptic region. My work with the Hearing Restoration Project is dedicated to optimization of gene transfer technology in the cochlea, and may assist in finding more detailed methods for NT3 gene transfer that better target affected cells.
More information on Dr. Raphael’s research can be found in his report, “Viral-mediated Ntf3 overexpression disrupts innervation and hearing in nondeafened guinea pig cochleae,” published in the journal Molecular Therapy—Methods & Clinical Development on August 3, 2016.
Yehoash Raphael, Ph.D., is the The R. Jamison and Betty Williams Professor at the Kresge Hearing Research Institute, in the Department of Otolaryngology–Head and Neck Surgery at the University of Michigan.