Preclinical Validation of Novel Fluorescently Labeled Compounds to Treat Neurodegenerative Hearing Loss
Abstract
Rationale: Hearing loss is the most common sensory deficit, affecting 600 million people worldwide, and the most common congenital anomaly, affecting 1 in 500 newborns. The most frequent type of hearing loss affects delicate mechanosensory and neural structures in the inner ear and is called sensorineural hearing loss (SNHL), which is also the most prevalent type of hearing loss (HL) after blast-related traumatic brain injury (TBI), as observed in Operation Iraqi Freedom Veterans. Similarly to chronic traumatic encephalopathy that characterizes TBI, a subset of SNHL is neurodegenerative HL, which is characterized by a disproportionally worse ability to discriminate speech than detect tones. Recent studies from our institution have demonstrated that neurodegenerative HL may be substantially more prevalent than previously recognized because even moderate acoustic trauma, previously assumed to cause only "temporary" HL, triggers degeneration of the auditory nerve without loss of sensory hair cells. Our recent data indicate that adolescent ears are particularly vulnerable to noise-induced neurodegenerative hearing loss, which may be relevant for military personnel who typically receive their basic training in their youth. Despite the magnitude of these problems, there are very few drugs that have shown efficacy in treating either TBI or SNHL. Currently, pharmacologic therapies for neurodegenerative HL are almost non-existent, and rehabilitation with hearing aids is typically unsatisfactory. We propose to explore a promising therapeutic strategy for neurodegenerative HL based on fluorescently labeled, biologically active bisphosphonates developed by our collaborating chemist. By extension, the proposed work has direct implications for treatment of neurodegenerative aspects of TBI within the central nervous system. Objectives: Our primary objective is to determine whether bisphosphonates, a class of well-tolerated drugs widely used to treat human osteoporosis and bone metastasis, can be repurposed for neurodegenerative hearing loss. We separately tackle restoration of synapses versus whole neurons using mouse model systems in vitro and in vivo. The in vitro model system is based on an organotypic culture of the cochlea treated with drugs to inflict selective loss of synapses or entire neurons. The in vivo model systems are based on utilizing noise to cause synaptic loss, or using a neural toxin to destroy neurons and thereby cause deafness. We are interested in drug repurposing as it expedites translation to human patients with hearing loss, for whom curative therapies do not yet exist. We will focus on bisphosphonates because our preliminary data from cultured cochlear neurons, Schwann cells, and stem cells suggest neuroregenerative effects of a bisphosphonate. By using fluorescently labeled bisphosphonates, we can shed light on the drug s mechanism of action so to define future therapeutic targets. Ultimate Applicability: By combining pharmacologic, histologic, molecular, biochemical, and physiologic tools, from single cell tracking to auditory performance, our study has a potential for rapid translation to humans suffering from neurodegenerative hearing loss. Our work also has direct implications for treatment of neurodegeneration in general, including that associated with TBI. Military Benefit: Hearing loss and the accompanying tinnitus are the most common disabilities reported in military Veterans. Cures for neurodegenerative hearing loss are essentially nonexistent. By stimulating neural regeneration, the proposed studies would outline strategies to promote not only hearing restoration, but also restoration of neurodegeneration in general, such as seen in TBI. Since bisphosphonates are already clinically approved in all major markets, our studies could lead to expedited approval to ameliorate neurodegeneration, and thereby benefit lives of Service members, Veterans, and their families.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510472
Entities
People
- Konstantina M. Stankovic
Organizations
- Massachusetts Eye and Ear Infirmary
- United States Army