Disabling hearing loss presently affects nearly half a billion people in the world. This figure is expected to increase to 2.5 billion people by 2050, with the associated economic cost estimated currently at approximately $800 billion. Despite these staggering statistics, the cellular basis of the most common type of hearing loss, called sensorineural hearing loss (SNHL), is unclear in living people. Consequently, available therapies are severely limited and there are no drugs FDA approved for the treatment of SNHL. Our research addresses these unmet medical needs through domain-specific customization and fusion of tools from molecular biology, bioinformatics, systems neuroscience, biotechnology, and otologic surgery. Our investigative efforts are organized along four main research thrusts: 1. Sensorineural hearing loss: disease mechanisms and biological therapies; 2. Vestibular schwannoma: pathobiology and therapeutics; 3. High resolution imaging of the inner ear; 4. Devices for inner ear stimulation and monitoring. Because our work is highly interdisciplinary, we also sustain additional medically-relevant projects.
To better understand molecular mechanisms underlying SNHL and inform future biological therapies, our research involves:
- Discovering molecular pathways that control hearing function
- Repurposing of drugs to restore sensorineural hearing
- Developing cellular models of human SNHL for mechanistic studies, high throughput drug screens, and therapy
- Gene therapy for SNHL
We have shown that zoledronate, currently used to treat osteoporosis and metastatic bone disease, can be repurposed to regenerate cochlear synapses. Our discovery that SARS-CoV-2 can directly infect human inner ear cells provides mechanistic insight into COVID-19-induced hearing loss, tinnitus, and dizziness. The surgical approach we developed for delivery of gene therapy to primate inner ear paves the way for rapid translation to people.
Vestibular schwannoma (VS), also known as acoustic neuroma, is an intracranial tumor that typically arises from a vestibular nerve and causes hearing loss, tinnitus, and dizziness. Our research addresses the current lack of FDA-approved drug therapies for VS and the associated hearing loss. The conventional thinking that VS causes hearing loss by mechanical compression of the adjacent auditory nerve fails to explain common clinical findings, such as that tumor size does not correlate with the severity of the tumor-induced hearing loss. Our laboratory has pioneered the field of systematic study of VS-secreted factors, and demonstrated that these factors contribute to VS-induced hearing loss. We have also shown that pathologic inflammation in VSs contributes to tumor-induced hearing loss, which can be prevented with losartan in a mouse model of VS. Our studies of molecular mechanisms of VS growth and hearing loss have culminated in our ongoing multicenter, prospective, randomized, double-blind, placebo-controlled phase II clinical trial of aspirin for VS.
Although the vast majority of sensorineural hearing loss (SNHL) can be traced to the inner ear, this organ has evaded cellular-level imaging in living humans because of its small size, complex three-dimensional anatomy, and encasement in the densest bone in the body, positioned deep in the base of the skull. We are developing optical tools for high-resolution imaging of cells in the inner ear to establish precise diagnosis and guide therapy, which is not yet possible clinically. We have demonstrated the feasibility of endomicroscopy of the human cochlea using a micro-optical coherence tomography catheter. The tiny, flexible imaging probes that we are building may also provide insight into cellular generators of tinnitus, as tinnitus typically originates in the inner ear and propagates into the brain.
We are developing novel devices for stimulation and sensing of the inner ear. The human inner ear has evaded diagnostic biopsy because of the physical constraints described above. Our research has provided key building blocks for future routine liquid biopsy of the human inner ear by defining the proteome of human perilymph, demonstrating the feasibility of detecting molecular markers of hearing loss in as little as 0.5 µl of inner ear fluid, and developing a novel microneedle device for controlled and reliable liquid biopsy of the human inner ear. Furthermore, we demonstrated that energy can be extracted from the biological battery in the inner ear to run electronics, without damaging hearing. We also developed a low-power prototype signal-processing chip for a fully implantable cochlear implant that can be wirelessly recharged using an ordinary cell phone.