Mark A. Rutherford, Ph.D.
Meet the Researcher
Mark A. Rutherford, Ph.D., received his doctorate in biology at University of Oregon, where he also did postdoctoral training. He was a postdoctorate fellow in auditory neuroscience at University of Göttingen in Germany before returning to Washington University in St. Louis, where he is an associate professor of otolaryngology–head & neck surgery. Rutherford is a 2027 Emerging Research Grants scientist, generously funded by Hyperacusis Research.
In 2025, I was invited to speak at the Belluci Symposium in Omaha where I met Steve Barad, M.D., who is the president of Hyperacusis Research. He told me that Hearing Health Foundation is particularly interested in pain hyperacusis research. I told him that those grants are intended only for early stage investigators. However, that policy has changed for topic-specific grants, like hyperacusis. So, I decided to propose to see if our “chemical earmuffs” small molecule therapy would work to prevent development of hyperacusis or mitigate active hyperacusis. We applied for funding and are grateful to have earned it.
I was drawn to science because it uses logic, unlike things like politics. I chose not to go to medical school because I didn’t want to listen to people complain all day (joking), but I do have some interaction with patients. Recently, a man with genetic hearing loss contacted me about developing a gene therapy. He had taken it upon himself to hire a company to create the virus. Now we are making a plan to test it in mice.
I wanted to be a podiatrist. In the 1990s, I’d gone to the computer lab to use their machines that ask questions and suggest a career. I cross-referenced “money” and “free time.” It told me to be a podiatrist. I like to go backpacking and camping in the wilderness. Once a year, my son and I go on a trip to the mountains in the summer. Some winters, we go skiing. I also love live music. I love music from the ’60s and ’70s. I saw the Grateful Dead with Jerry Garcia four times in high school. Eventually, I like the idea of managing my lab remotely half-time from my house in the mountains.
The Research
Washington University in St. Louis
Preventing or mitigating hyperacusis with blockade of calcium-permeable AMPA receptors
Pain hyperacusis is an abnormal sound level tolerance associated with increased activity in the central auditory system. It can be caused by damage to the inner ear that is not detected on a typical hearing test. This type of damage is associated with permanent loss of cochlear nerve fibers. Paradoxically, in some patients this decrease in cochlear function leads to an increase in the brain’s sensititivity to sound. We have developed a therapy in mice to prevent loss of nerve fibers during noise trauma by inhibiting the synaptic communication between the cochlea and the auditory nerve. Importantly, animals can still hear during the protection because the communication is not blocked entirely. However, it is not known if preventing cochlear nerve loss would prevent the development of hyperacusis. We call our therapy “chemical earmuffs.”
The brain also has synapses that are inhibited by our chemical earmuffs. However, it is not known if inhibiting those could mitigate hyperacusis after it has emerged. If loss of input to the brain is responsible for the increase in activity in the central auditory system, then preventing this loss could prevent hyperacusis in the first place. If overactivity in the brain depends partly on activation of synapses inhibited by chemical earmuffs, then blocking them could mitigate active hyperacusis. Our small molecule therapy works when given systemically because it enters the inner ear and the brain from the blood. In this proposal, we hypothesize that (1) Preventing loss of cochlear nerve fibers will eliminate the development of hyperacusis, and (2) Giving our therapy to animals with hyperacusis will mitigate hyperacusis-associated phenotypes.
Long-term goal of research: Upon discovering the abundance of CP-AMPARs on the postsynaptic densities of auditory nerve fibers in the cochlea, we showed that blocking them with commercially available polyamine compounds is sufficient to prevent noise-induced synaptopathy. Our subsequent finding of the drug-like properties of IEM-1460 and IEM-1925 prompted us to initiate a drug discovery project aimed at developing analogs of those polyamines. In order to treat or prevent hyperacusis or other disorders of glutamate excitotoxicity safely, the new compounds must: (1) retain the pharmacological properties of selective blockade of CP-AMPARs, (2) be sufficiently distinct in structure to enable protection of intellectual property, (3) retain the drug-like property of systemic bioavailability, and (4) be non-toxic at efficacious doses.
Over the past five years, with Department of Defense funding, we have designed, synthesized, and tested approximately 200 novel compounds in collaboration with the Washington University Center for Drug Discovery. We achieved our goal of finding novel compounds that are similar to IEM-1925 but distinct enough to be patented, and we are now working with our office of technology management. In anticipation of the patent, we have formed a company called Neuroguard LLC to license the technology, to facilitate industry partnership, and to enable small business innovation research grant applications. In one way or another, further development of our novel Neuroguard compounds requires significant investment in our program.
One of the reasons there is no drug for noise-induced hearing loss is that clinical trials for hearing loss are lengthy and expensive. In the case of cochlear synaptopathy, in which hearing disorders may be underpinned by reduction of cochlear output (reduced ABR wave-1) without “hearing loss” defined clinically by threshold elevation, the clinical endpoint is difficult to measure and not universally accepted. However, subclinical “hearing loss” may be accompanied by comorbidities such as tinnitus and hyperacusis which can be subjectively reported by patients. Hyperacusis, particularly pain hyperacusis, can be a severely debilitating disorder for which there is currently little or no effective therapy.
If we can show that IEM-1925 is able to prevent or mitigate hyperacusis in mice, then we will be able to publish valuable information to attract investment in our drug development program. In unpublished studies, we have found that our novel compounds work like IEM-1925. The indication of hyperacusis will attract investment to bring our novel compounds to the next level of development, toward investigational new drug (IND) status. Expensive IND-enabling studies are necessary to move our technology toward clinical trials. With the success of this project, Hyperacusis Research and Hearing Health Foundation will have provided the resources needed to advance our program to the next stage of translation toward a clinical solution for pain hyperacusis.
