Toward a Precision Medicine Approach for Tinnitus

Thanos Tzounopoulos, PhD, is working to conquer the mysteries and complexities of tinnitus. As professor and vice chair of research in the Department of Otolaryngology, and as UPMC Endowed Professor of Auditory Physiology and director of the Pittsburgh Hearing Research Center, Dr. Tzounopoulos’ basic and translational studies have provided significant new insights in recent years with respect to the pathological and mechanistic drivers of this common, highly heterogeneous, and often disabling condition.

About 10 to 15 percent of the entire U.S. population has experienced some variation and degree of tinnitus, with nearly 10 million seeking out medical care for the condition. Upwards of 2.5 million individuals are debilitated by the condition with severe effects on their quality of life. “We have no cure and limited therapies that can provide relief for these individuals. But we are making progress in understanding the cellular and molecular mechanics of what triggers the condition, and how we may be able to intervene pharmacologically,” says Dr. Tzounopoulos.

In tinnitus, there is usually a triggering event, for example an acoustic trauma such as an explosion or prolonged exposure to high levels of sounds, or age-dependent hearing loss, that set off a cascade of events — some known, others still a mystery — that leads to an individual’s experience of the condition which can be highly variable, from mild to outright unbearable. Additionally, there are mechanisms that work from a maintenance perspective that allow the continuation of the tinnitus leading to a permanent presence. Much of Dr. Tzounopoulos’ research has been focused on the triggering mechanisms and molecular changes that occur in the brain, and how to intervene at an early stage to cut short and prevent a long-term or permanent manifestation of the condition.

Dr. Tzounopoulos’ and colleague’s research over the last 10 years has uncovered, among other aspects, a specific class of potassium channels responsible for the onset process of tinnitus. His work also has shown that modulation of this channel in his murine model of tinnitus via pharmacological intervention can prevent the development of the condition.^1,2,4

Working in collaboration with University of Pittsburgh chemist Peter Wipf, PhD, Distinguished Professor and director of the Combinatorial Chemistry Center and the Center for Chemical Methodologies and Library Development, the duo has discovered and continues to actively investigate the ability of a potassium channel activator known as RL-813 — derived by them from the compound retigabine, an epilepsy medication — that may be able to function as a treatment for tinnitus because of its ability to target the potassium channel associated with the condition. Initial studies are underway in preclinical animal model trials.

In order to further the research into the mechanistic causes of tinnitus, and to define more accurately what will likely be numerous phenotypes of the condition, ultimately establishing an evidence-based differentiation of tinnitus and its underlying mechanisms, Dr. Tzounopoulos has assembled a team of multidisciplinary researchers from the University of Pittsburgh and Carnegie Mellon University to investigate and collaborate to develop new models of care.

“As it currently stands, tinnitus is thought of as being idiopathic or secondary in nature. We do not have a systematic characterization of the different paths of tinnitus,” says Dr. Tzounopoulos.

These new efforts aim to establish a path for replacing the empirical classification of tinnitus with a taxonomy from precision medicine. The goal of a classification system is to understand the inherent heterogeneity of individuals experiencing and suffering from tinnitus, and to identify what differentiates potential subgroups.

More importantly this differentiation will reveal what the members of a subgroup share in common based on the network, cellular, and molecular properties of their peripheral and central auditory and nonauditory networks involved in tinnitus. As such, this classification requires the understanding of the underlying mechanisms of tinnitus and will lead to a mechanistic-driven personalized medicine approach to the care of tinnitus patients.

“The goal is to move to a precision medicine approach because different patients, based on the damage that they have, are going to need different kinds of treatment. This is no different than, for example, how we are starting to conceive and approach other diseases, for example, cancer. This effort will be a first of its kind with respect to the study and treatment of tinnitus,” says Dr. Tzounopoulos.

Zinc is a critically important micronutrient that facilitates the function of thousands of proteins in the human body. Unbound zinc has been shown in recent years to act as a neurotransmitter in the brain in concert with glutamate. This has turned out to be an important process in the auditory cortex in the brain where this unbound form of zinc is responsible for modulating or adjusting the responsiveness of the brain to sound through a process called gain modulation.5

Dr. Tzounopoulos’ research group was the first to identify this role of zinc in the auditory cortex. “It has revolutionized a part of my research, because we have been able to unmask the role of zinc in the auditory cortex and how it affects how we perceive sound.”

Neurosurgery

Robert M. Friedlander, MD — Chairman, Department of Neurosurgery

ENT Physicians

Jonas Johnson, MD, FACS — Chairman, Department of Otolaryngology

Candace Hobson, MD — Department of Otolaryngology

Audiologists

Catherine Palmer, PhD — Department of Otolaryngology

Lori Zitelli, AuD — Department of Otolaryngology

Psychoacoustician

Christopher Brown, PhD — Department of Communication Science and Disorders

Neuroscientists

Dean Salisbury, PhD — Department of Psychiatry

Avniel Ghuman, PhD — Department of Neurological Surgery

Karl Kandler, PhD — Department of Neurobiology

Thanos Tzounopoulos, PhD — Department of Otolaryngology

Bharath Chandrasekaran, PhD — Department of Communication and Science Disorders

Maria Rubio, MD, PhD — Department of Neurobiology

Psychophysicist

Lori Holt, PhD — Professor, Department of Psychology, Carnegie Mellon University

1 Li S, Choi V, Tzounopoulos T. Pathogenic Plasticity of Kv7.2/3 Channel Activity Is Essential for the Induction of Tinnitus. PNAS. 2013; 110(24): 9980-9985.

2 Li S, Kalappa BI, Tzounopoulos T. Noise-Induced Plasticity of KCNQ2/3 and HCN Channels Underlies Vulnerability and Resilience to Tinnitus. eLife. 2015.

3 Kumar M, Reed N, Liu R, Aizenman E, Wipf P, Tzounopoulos T. Synthesis and Evaluation of Potent KCNQ2/3-Specific Channel Activators. Mol Pharmacol. 2016; 89(6): 667-677.

4 Kalappa BI, Soh H, Duignan KM, Furuya T, Edwards S, Tzingounis AV, Tzounopoulos T. Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus. J Neurosci. 2015; 35(23): 8829-8842.

5 Anderson CT, Kumar M, Xiong S, Tzounopoulos T. Cell-Specific Gain Modulation by Synaptically Released Zinc in Cortical Circuits of Audition. Elife. 2017; 9(6).

• U.S. Army-DOD, Tzounopoulos and Wipf. W81XWH18-1-0623, Development of a Novel Pharmacotherapy for Tinnitus, September 2018 – August 2021

• NIH, Tzounopoulos, Cell-Specific Synaptic Plasticity in the Auditory Brainstem, 5R01 DC007905, March 2016 - February 2022

• NSF, Tzounopoulos and Aizenman, NSF-IOS-BSF: Influence of neuronal zinc homeostasis on cortical responses to sound, IOS-1655480, September 2017 - July 2021