Project Description: Hearing loss is the most common sensory disability. It affects 0.3 per cent of newborns, 5 per cent of people under age 45, and 50 per cent by age 70, and impacts 400 million people worldwide. In the mammalian cochlea, primary auditory neurons (PAN) are responsible for transmitting auditory information from the mechanosensory hair cells in the cochlea to the brainstem. PANs do not regenerate; thus, when they are lost or damaged due to noise exposure or aging, their loss is prevalent and permanent, and leads to hearing impairment. The development of methodologies that could be used to induce the regeneration of auditory neurons in a damaged ear, therefore, has significant implications for future advances in the treatment of hearing loss. The potential clinical value of the regenerative therapy in the amelioration of hearing impairment is tremendous. The approach proposed in this project for hearing loss treatment is to use gene therapy, which offers rigorous methods for characterization of functional recovery. Several cochlear gene therapy studies have focused on preserving PANs by gene transfection of neurotrophins, showing the feasibility of gene therapy for protection of PANs and regrowth of neurites to cochlear hair cells peripherally. Direct cell reprograming is an emerging area of regenerative medicine and, as proof of principle, Dr. Dabdoub and his team have successfully induced neurons by overexpression of transcription factors in non-sensory epithelial cells in the inner ear. Herein, they propose to convert endogenous glial cells that normally surround PANs and survive after neuron loss, into regenerated PANs. The ultimate goal is to induce PANs in human ears to enable functional innervation to both the cochlear nucleus in the central nervous system and hair cells or cochlear implants in the periphery. The induction of even a small number of neurons in a damaged ear has significant implications for clinical research related to cochlear implants and hearing restoration, because as few as 10 per cent (3,500) of the congenital normal number (35,500) of PANs could result in auditory sensation.