Research Project
9346979
PROJECT SUMMARY PROBLEM: Hearing loss is the most common sensory disorder in human populations across the globe, affecting an estimated 50 million people in the United States and 360 million people worldwide. As a primary means of interpersonal communication, hearing is central to daily life and its loss can have dramatic impact on cognitive development in children, mental health in adolescents and adults, contribute to dementia in the elderly, and can result in an overall increase in mortality. There are currently no drugs approved for the treatment of hearing loss caused by damage to the sensory cells of the cochlea or to the auditory nerve (sensorineural hearing loss). A major barrier to the development and evaluation of promising new therapies is the inability to deliver macromolecules or complex regimen of small molecules to the sensory cells of the cochlea. NEED: There is a pressing need for a delivery system that can safely and reliably distribute a range of therapeutic modalities to the sensory epithelium along the length of the cochlea. GOAL: The goal of the proposed studies is to develop a novel cochlear delivery system and quantify its distribution and safety profile in a large animal model. COMPANY?S TECHNOLOGY/PRELIMINARY DATA: Akouos is building off of a decade of work studying drug distribution in the cochlea. This work has informed key design parameters of a robust delivery system, including infusion volumes and flow rates that can be safely tolerated, and have uncovered unanticipated barriers to broad distribution in vivo. Based on these prior studies, we have designed and built an acute delivery system capable of delivering a wide range of molecules, including macromolecules and nanoparticles, directly to the cochlea via the round window membrane. AIMS: Here, we propose studies to refine key device parameters and a surgical procedure for application in a sheep model that closely resembles human middle and inner ear anatomy. Further, we propose a distribution and safety study of the delivery system to demonstrate effective distribution of adeno-associated virus (AAV) particles along the basal-apical axis of the cochlea in the sheep model. The proposed project will demonstrate that an acute delivery system can safely and reliably deliver macromolecules throughout the cochlea, and thereby provide a means to test novel therapies that have the potential to prevent and reverse hearing loss due to multiple causes . MILESTONE: A delivery system that can distribute AAV particles to achieve transgene expression that differs no more than 50% from cochlear base to apex in a large animal model, without significantly increasing hearing thresholds. WHAT?S NEXT: At the successful conclusion of this Phase I SBIR, we will be poised to move forward into IND-enabling studies with a gene therapy candidate to support human clinical trials for a form of monogenic deafness. Phase II of the SBIR proposal will fund a confirmation proof of concept study in a transgenic disease model, as well as a GLP toxicity study in a large animal model.
