Research in the department currently focuses on identifying genes that are critical for hearing through the use of molecular genetic and molecular biologic methods, and investigating the use of virally mediated gene therapy to regenerate spiral (cochlear) ganglia—nerve cells that transport sound from the cochlea to the brain—in order to enable the sense of hearing in children born with genetic forms of hearing loss.

Clinical studies in age-related hearing loss are underway to address one of the world’s emerging public health problems. More than 80% of those over 85 years of age have hearing loss. As the average human lifespan increases, it will become even more important to preserve the senses. This will allow increased quality of life and may also reduce associated conditions such as social isolation, depression, and dementia.

Faculty Active in This Area

Active Research

Mechanisms Linking Hearing Loss and Dementia

PrincipaI Investigator: Justin Golub, MD

Cognitive impairment (CI) is increasing in prevalence and burden. Dementia may reach 32% in those ≥85 years old. In 2016, 5.4 million (1 in 8) US elders, had dementia, with $221 billion in costs. Despite increased understanding of Alzheimer’s disease pathology, no preventive or curative measure exists and new agent trials are discouraging. Age-related hearing loss (ARHL) begins in middle age12 and is caused by loss of inner ear neurosensory cells. ARHL loss is irreversible, progressive, and near-universal in later life. Treatments include amplification with hearing aids or, if severe, cochlear implants. Treatment levels are poor, at 25% in those 80 years old. Hearing loss (HL) and CI are two common disorders of aging that appear to be related, but whether the association is causal, and the mechanism explaining this association, are unknown. The proposed project will explore the relation of hearing loss (HL) to Alzheimer’s disease (AD) and related dementias (ADRD).

Hearing Loss and Depression/Cognitive Decline in the Elderly

PrincipaI Investigator: Ana Kim, MD

Hearing loss is a prevalent consequence of aging and poses special challenges for older adults. Particularly when superimposed on other age-related conditions, age related hearing loss (ARHL) places older adults at risk for social isolation and negative health outcomes in the psychosocial and physical domains of function. ARHL is associated with depression and reduced quality of life. The purpose of this study is to determine if hearing aid use and/or antidepressants are effective in increasing quality of life for this population.

A multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of 2 dose regimens of orally administered SENS-111 (100 mg and 200 mg) given during 4 days in patients suffering from acute unilateral vestibulopathy

PrincipaI Investigator: Ana Kim, MD

Acute unilateral vestibulopathy (AUV) (previously called acute vestibular neuritis) is the third most frequent cause of peripheral vestibular vertigo, after benign paroxysmal positional vertigo and Menière’s disease. It is caused by a sudden unilateral isolated vestibular deficit. The annual incidence is about 3.5 to 15 cases/100,000 according to sparse epidemiological data. Clinically, AUV is a severe condition, characterized by an acute or subacute onset of severe sustained spinning vertigo associated with nystagmus, postural and gait unsteadiness, nausea and often vomiting. There is no acute hearing loss, tinnitus, and no other neurological symptoms. Patients are unable to cope with their usual daily activities. Most symptoms usually abate spontaneously within several days but they may last one or two weeks. AUV occurs usually once during the life span. It is estimated that about 40% of patients will suffer from sequelae: long term unsteadiness and benign paroxysmal positioning vertigo (15% of patients) The goal of this study is to look at the effects of a new drug (SENS-111) in controlling the acute vertigo and other symptoms related to AUV more rapidly and in limiting the long-term residual symptoms.

Intracochlear Delivery of Therapeutics Across RWM via Microneedle Array

Principal Investigators: Jeffrey W. Kysar, PhD and Anil K. Lalwani, MD

The cochlea is a common site for clinical pathology in our modern society. Tens of thousands of Americans are affected every year by inner ear diseases such as Meniere’s, sudden sensorineural hearing loss (SSNHL), and tinnitus. If not treated properly and in a timely manner, these illnesses can have a debilitating, chronic effect on one’s hearing or balance, and significantly decrease their quality of life. Unfortunately, the cochlea is surrounded by one of the hardest bones in the body, and is quite difficult to reach anatomically. Some currently available treatments for these diseases are limited by their reliance on the medications to reach the inner ear via the bloodstream or through simple diffusion from the middle ear, while others necessitate making destructive holes in the cochlear bone and breaching the scala tympani. Thus, to date no method exists to provide effective, precisely dosed delivery of inner ear therapeutics without risking permanent damage to one’s hearing. To circumvent this barrier, the researchers aim to create micro-perforations through the ear’s natural round window membrane (RWM) to access the inner ear fluid for drug delivery. The mechanical properties of this border between the middle and inner ears will first be explored to deepen the scientific understanding of the RVM. Techniques such as nanoindentation, laser interferometry, digital microscopy, micro CT (uCT), and high fidelity finite element modeling will be utilized for a complete picture of the RWM properties under both local and global pressures throughout the process of perforation. Based on the results of these studies, various arrays of both solid and hollow silicon microneedles will be designed using isotropic etching and cryogenic processes. These needles will first be tested for their propensity to buckle or bend, and needle design will be optimized for safety during RWM perforation. A series of in vitro then in vivo studies will follow, using guinea pigs as an appropriate animal model. These studies will assess the ability of temporary solid micro-perforations or microinjection systems through implanted hollow needles to reliably increase the permeability of the RWM. The effect of these needles on RWM histology, the ability of the RWM to heal post-perforation, and the impact of the needles on guinea pig hearing will also be assessed. Finally, the perforations will be analyzed for their ability to consistently provide precise intracochlear drug concentrations. Our animal studies will be followed by the same studies in in vitro, fresh human temporal bone samples, with the ultimate goal of creating a manual mechanical device to deliver micro-perforations in clinical trials. Once optimized for the specific properties of the human RWM, such a device could allow for safe, quick, effective perforations into the inner ear in the clinic. With the use of hollow needles, this device could both sample inner ear perilymph and inject medications when necessary, opening up a new realm of inner-ear diagnostics while then providing a means of precise, personalized treatment of often previously idiopathic inner ear pathologies.

A three-part, multicenter, open label, single dose study to assess the safety, tolerability, and efficacy of intra-labyrinthine (IL) CGF166 in patients with severe-to-profound hearing loss

PrincipaI Investigator: Lawrence Lustig, MD

Sensorineural hearing loss and vestibular dysfunction may result from destruction of inner ear sensory hair cells and/or auditory nerves. Humans are born with ~30,000 sensory hair cells. Sensory hair cells are critical for auditory function while vestibular sensory hair cells located in the vestibular canals and the utricle and saccule provide the basis for vestibular function. Sensory cells can be damaged or destroyed by pharmacological agents (chemotherapy and aminoglycosides), loud noises, infections or simply aging and loss of these cells is permanent as they do no regenerate. Hearing loss is currently treated with a hearing aid or a cochlear implant in patients with severe impairment; patients are eligible for a cochlear implant when they have severe to profound hearing loss with the inability to discriminate 40% of speech. Approximately 188,000 people worldwide have received cochlear implants. Cochlear implants improve auditory function but require invasive surgery, require ongoing maintenance and patient training; they also are expensive. The purpose of the study is to evaluate the safety, tolerability, and the potential ability of CGF166 delivered through IL-infusion to improve hearing and vestibular function.

Genetic Analysis of Hearing Loss

PrincipaI Investigators: Lawrence Lustig, MD and Ana Kim, MD

Hearing loss is the most common sensory abnormality in humans, affecting over 50% of patients greater than 70 years of age. Loss of hearing is associated with a number of human maladies, including strained social interactions, isolation, depression, and an increase in cognitive decline and dementia. To date, approximately 50 single gene defects have been identified that lead to hearing loss and it is estimated that the total number of genes involved in hearing loss is over 100. While many of the simple single gene defects have been discovered, defects involving multiple genetic loci are harder to ascertain. However, with the advent of next-generation sequencing technologies, our ability to identify even subtle genetic variants that lead to hearing loss is becoming a reality. The purpose of this study is to examine the DNA of research subjects and their family members in order to identify genetic causes and contributors to hearing loss. In addition, we are investigating the possible link between sudden hearing loss and genetics.