Trk Agonist Antibodies for the Treatment of Hearing Loss
Abstract
A major underlying cause of hearing loss across many demographic regions is exposure to excessive noise, known clinically as noise-induced hearing loss, or NIHL. The incidence of NIHL is high among United States Military personnel and hearing disorders are the most common service-related disability among U.S. Veterans. Also, it is estimated that 26 million adults between the ages of 20-69 develop a high frequency NIHL from work or leisure activities; however, the overall prevalence of hearing impairments is 30% greater among Veterans than the lay public. In addition, continued intermittent exposure to high-decibel noises (gunfire, machine noise, music) can result in sound perception deficits despite normal hearing tests, a syndrome known as hidden hearing loss (HHL). Currently there are no effective drugs to treat hearing loss, despite past and current efforts. Therefore, safe and effective ways to treat NIHL or HHL will improve the quality of life for thousands of Veterans and the lay public and substantially reduce the disability costs incurred by the VA and the healthcare system in general. Excessive noise exposure causes the loss of connections between hair cells that sense sound waves and the neurons that relay that sound information to the brain. Loss of these critical connections is referred to as "synaptopathy." Results from studies in rodents and in human tissue have shown that certain protein growth factors known as neurotrophins may be able to restore and regenerate noise-damaged neurons and cells involved in our ability to hear. These growth factors bind and activate molecules on the surface of sensory cells of hearing known as Trk receptors. Zebra Biologics, Inc. has now discovered superior pharmaceutical versions of these neurotrophin growth factors that bind to Trk receptors, using recently patented technologies to make what are known as "agonist antibodies" that activate Trk receptors. The goal of the studies proposed in this grant application is to discover new Trk agonist antibody drug candidates to treat synaptopathy and other underlying disease mechanisms of hearing loss. We will determine the optimal molecules for testing in animal models of NIHL, and also for eventual human use. Through the course of this proposal we will explore practical ways to effectively deliver these biologic drugs to the region of the ear known as the cochlea. Ultimately, we intend to move our discoveries from the laboratory through to clinical development. Discoveries emanating from this proposal will represent a clear milestone toward an understanding of the mechanisms involved in noise-induced damage and offer treatments for a significant neurological problem where none exists currently. Furthermore, we hope to make our Trk agonist antibodies available to the scientific community so that they may use these as research tools to understand the mechanisms underlying hearing disorders and possibly other neurological diseases. Other causes of hearing loss affect a significant number of individuals, as well. In addition to NIHL, a large proportion of the elderly population suffers from age-related hearing loss (known as presbycusis), where degeneration of cells of the inner ear is thought to underlie deafness. Drugs such as the aminoglycoside class of antibiotics and the anti-cancer drug cisplatin also cause significant hearing loss. In addition, countless genetic mutations also result in forms of deafness, particularly in children. As with NIHL, limited therapies exist to treat these other forms of hearing loss and outcomes from the research planned here will serve as treatments for these types of hearing loss as well. The ability to hear is one of the most important modes of sensation to all mammalian species. Regardless of the type of hearing deficit, the quality of life for those afflicted is diminished significantly when this important sensory modality is threatened. Our mission is to arm physicians with groundbreaking
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010787
Entities
People
- Peter Distefano
Organizations
- United States Army
- Zebra Biologics (United States)