Treatment of Cochlear Synaptopathy
Abstract
Degeneration of neural circuitry through synaptic loss is an important cause of nervous system dysfunction, and afferent auditory synaptic loss leading to deafness or hearing impairment is a manifestation of these processes occurring in the cochlea. In previous work, we have shown that neurons that remain after synaptic damage can be recruited to form new synapses by modulation of Trk receptors using NT3, BDNF, and amitriptyline, a small molecule Trk agonist, and by inhibition of pathways that prevent synaptic regeneration with an antibody against repulsive guidance molecule a (RGMa). In this proposal, we ask whether a bisphosphonate drug and a Trk agonists work together to repair the synapse; we assess the effect of the timing of treatment relative to the acoustic insult on achieving synaptic repair; and we investigate the degree of synergy achieved by stimulating regrowth of neurons while also overcoming blocks to regeneration of neurons. Measurements of synaptic repair include quantitative analysis of new synapses, which is performed both in vitro and in vivo, and physiological assessments of peripheral auditory function. Repair of neural connections to hair cells in the adult ear is important for therapeutic approaches to the treatment of neural dysfunction that causes hearing loss. The Specific Aims comprise three important experiments to translate these findings to a clinical agent for the peripheral reinnervation of the auditory system. In Aim 1, we attempt to determine the molecular mechanisms through which a Trk agonist and a bisphosphonate drug drive the reinnervation of hair cells in a cochlear model of afferent synapse loss in vitro. In Aim 2, we study synaptic repair in an in vivo system in which afferent synapses are lost due to noise exposure: the experiments look at the effects of Trk agonist and a bisphosphonate drug on synaptogenesis and at the time-window in which these approaches are effective. The effects of combining TrkB agonist and bisphosphonate drugs will be correlated to brainstem response, distortion product otoacoustic emissions, and the morphology and number of synapses formed with inner hair cells determined immunohistochemically. In Aim 3, we test the pharmacokinetics and safety of the drug in the guinea pig after round window membrane application of a Trk agonist (amitriptyline) or subcutaneous administration of a bisphosphonate (zolederonate). Because of the clear correlation between loss of synapses and sensorineural hearing loss, improvements in our ability to regenerate afferent synapses with hair cells will lead to treatments for hearing loss. These treatments will be useful for the military because of the prevalence of noise-induced hearing loss. We expect that this new approach to ted synapses can enter clinical trials by the within the time period of this 3-year study.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210554
Entities
People
- Albert Edge
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army