Development of New Therapies that Stimulate Hair Cell Regeneration
Abstract
One of the most prevalent casualties in military settings is hearing loss resulting from exposure to either intense or prolonged exposure to loud noise. This type of noise-induced hearing loss is caused by the death of ultra-sensitive cells in the inner ear whose job is to detect noise vibrations and convert them into signals that the brain can perceive as sound. On average, humans have about 12,000 of these specialized cells (called hair cells) at birth and they are never replaced, meaning that damage to any one of them is permanent and accumulation of this damage over one s life causes deterioration of hearing. Moreover, once an ear has suffered from hearing loss, it becomes further sensitized, which speeds up the progression of hearing loss over time. It is therefore essential to reverse this hair cell damage to preserve current and future hearing. While hearing aids can provide some limited benefit, they do not repair the inner ear structures nor are they practical for use in all settings, such as military deployments, and they also need constant maintenance and upkeep. There are currently no U.S. Food and Drug Administration-approved drugs for the treatment of hearing loss, and only two drugs for hair cell regeneration have even reached clinical trials, but thus far the results have shown limited to no benefit. There is thus a significant need to enhance our ability to evaluate and screen new drugs to ensure they have regenerative properties and can successfully restore hearing and hair cells in animal models before being applied to humans in clinical trials. It was first discovered over 35 years ago that birds, fish, and amphibians can regenerate their hair cells after damage to restore hearing, although this ability is completely lost in humans and other mammals. In the birds, fish, and amphibians, regenerated hair cells are derived from adjacent supporting cells that can either directly convert into a hair cell after damage or can duplicate themselves and then convert one of the new cells into a new hair cell. However, in lab experiments it is easy to confuse hair cell regeneration (replacing a dead cell) with just hair cell protection (preventing the cell from dying in the first place) since it can be difficult to identify a new from an old hair cell. In order to confirm that regeneration has occurred, it is thus necessary to be able to track the trajectory of these supporting cells, which can be done using unique strains of mice that are bred such that supporting cells in the inner ear will be marked with a red fluorescent protein that can be visualized under a microscope and any cell derived from one of these red supporting cells will also carry that same red protein. So in studying hair cell regeneration, one can easily identify a new hair cell that arose from a supporting cell by the presence of both hair cell proteins as well as the red supporting cell marker. In this proposal we combine this tracing strategy with an inner ear model for screening drug compounds with regenerative properties, thus yielding a very specific screen with clear outcomes and increasing the likelihood of finding compounds with therapeutic potential. The compounds we propose to screen have been carefully selected using proprietary computer-assisted learning algorithms designed to mine both the literature archives and compound libraries on the internet and represents a unique and targeted selection, which further increases the likelihood of identifying good drug candidates. This proposal is further enhanced by the partnering of an academic laboratory with a well-known track record in regenerative research with a pharmaceutical company with over 10 years of experience in drug development for targeted delivery to the ear for hearing disorders. This strategy thus facilitates the rapid movement and navigation of any identified drug hits through the required pharmaceutical development stages to quickly bring a new drug from
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210674
Entities
People
- Brandon C Cox
Organizations
- Southern Illinois University School of Medicine
- United States Army