Preclinical Validation of Novel Fluorescently Labeled Compounds to Treat Neurodegenerative Hearing Loss
Technical Report,15 Sep 2015,14 Sep 2016
Massachusetts Eye and Ear Boston United States
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Background The proposed research addresses a FY1415 CRMRP NSRRA focus area on hearing loss, with a specific focus on neurodegenerative hearing loss, which commonly accompanies traumatic brain injury TBI. There is an unmet medical need to develop pharmacologic therapies for hearing loss. We address that need, and the focus area on preclinical research to restore function, by studying a neuroregenerative potential of bisphosphonates, which are FDA-approved for the treatment of bone diseases such as osteoporosis. By utilizing drug repositioning, we expedite translation of our research to a potential future clinical trial. Our research also indirectly addresses the focus area of pain management because metabolites that we study are known to mediate pain. Our experiments test the hypothesis that bisphosphonates promote cochlear synaptogenesis and neurogenesis, and that this regenerative effect is mediated by ERK inhibition and decrease in farnesyl pyrophosphate FPP and geranylgeranyl pyrophosphate levels GGPP. Progress We have developed an in vitro model to study synaptopathy based on application of kainic acid to murine cochlear explants. We have used this model to begin studying synaptogenic potential of a specific bisphosphonate, zoledronate, in vitro. In parallel, we have developed and published a mouse model of cochlear synaptopathy in vivo. Using this model, we have obtained preliminary data demonstrating a synapthogenic potential of zoledronate in vivo. Because bisphosphonates signal via ERK, whose activation is affected by osteoprotegerin OPG, we studied and described, for the first time, cochlear expression of OPG-related molecules TNF-related apoptosis-inducing ligand TRAIL and its signaling death receptor 5 DR5. With an eye toward an ultimate clinical trial, we have studied limitations of current audiograms in predicting specific cellular damage, and have identified optical tools that have a potential of quantifying neuronal damage in vivo.
- Medicine and Medical Research
- Anatomy and Physiology