Aminoglycoside antibiotics are considered an essential group of medications by the World Health Organization. Each year, thousands of children and adults are prescribed aminoglycosides to treat severe gram-negative bacterial infections. This is especially prominent in the neonatal intensive care units, where over 80% of the neonates are prescribed aminoglycosides. Unfortunately, administration of aminoglycosides carries substantial risk for life altering side effects, namely irreversible hearing loss. This is especially evident in the fact that 15 out of every 100 neonates will experience hearing loss, as compared to the 1 to 3 out of every 1,000 babies who are born full term. Hearing loss alters an individual?s ability to communicate and is associated with feelings of isolation and depression. Substantial effort is still required to identify the first FDA approved therapeutic for prevention of aminoglycoside related ototoxicity. We are proposing this study with the long-term goal of providing a therapeutic to combat this ototoxic side effect. To date, we have collected promising preliminary data suggesting momelotinib, a drug currently with FDA fast track designation, could be repurposed for this use.
In Aim 1, we will use an aminoglycoside treated sepsis mouse model to provide preclinical, functional hearing data on the ability of momelotinib to prevent aminoglycoside induced hearing loss. In our experiments proposed in Aim 2, we will utilize the well-established and translatable zebrafish model organism to identify the essential targets and mechanisms of hair cell protection by momelotinib. This project advances the mission of the NIDCD to promote interventions to treat communication and other disorders. Specifically, our mechanistic studies in Aim 2 address Priority Area 2 in Hearing and Balance Research to increase the understanding and pathogenesis of ototoxicity. In addition, our characterization of momelotinib as a promising preventative treatment for aminoglycoside induced hearing loss advances Priority Area 3, to improve the diagnosis, treatment, and prevention of hearing loss through the development therapies to resist cell damage. This project will be completed at Creighton University under the sponsorship of the well-established auditory scientist, Dr. Jian Zuo. Creighton University has a strong history of auditory research. It houses a Translational Hearing Center dedicated to research pursuits in the therapeutic prevention of hearing loss and hearing restoration through hair cell regeneration. The physician-scientist program at Creighton University provides a well-rounded, integrated curriculum and tailors educational and clinical experiences to each student and their career aspirations. Specifically, the gateway program and longitudinal clinic provide great opportunities for students to gain exposure to the field they are going to enter. There is also a clinical refresher course offered during the last year of research training, which will ease the transition of the students back into the clinic. Overall, the strong auditory research community, unique training environment and impactful research project, ensures that my time at Creighton University will facilitate my development to become an independent physician-scientist in the field of otolaryngology.
Aminoglycosides represent an indispensable class of antibiotics that have saved countless lives from severe bacterial infections however, their use is associated with several adverse effects including irreversible hearing loss. In this study, we will investigate momelotinib, a potential therapeutic for aminoglycoside induced hearing loss, as well as investigate the specific molecular targets of the drug that results in the prevention of hearing loss through the protection of sensory hair cells. This study will provide necessary preclinical data for this promising drug candidate to be used to prevent aminoglycoside induced hearing loss.
