Hearing loss is one of the most common forms of sensory deficits affecting humans, and noise-induced hearing loss (NIHL) affects members of the military more prevalently than the general population. There is no pharmaceutical treatment for hearing loss which presents as an urgent and major unmet medical need. Different factors contribute to hearing loss including genetic defects, environmental factors (noise and ototoxic drugs), and aging. Damage to and loss of hair cells, the inner ear sensory cells that detect sounds, is the major cause of hearing loss. The human inner ear, like other mammalian inner ears, lacks the capacity to regenerate hair cells spontaneously after hair cell loss, which makes hearing loss permanent.

By co-activating genes of Myc and Notch1, we demonstrated that they are sufficient to reprogram the adult mouse inner ear for renewed proliferation. Significantly reprogrammed mature inner ear cell types regain the capacity to respond to hair cell induction signals and become (transdifferentiate into) hair cells, in cultured mouse inner ear and in live mice in vivo. Regenerated hair cells are able to make connections to ganglion neurons, which is required to transmit the signals converted from sound stimuli into electric impulse to the brain. This work demonstrates the feasibility of using reprogramming to achieve hair cell regeneration in the fully mature mammalian inner ear, which is prerequisite to the application in humans as even the newborn human inner ear is fully mature. The work opens the possibility of using hair cell regeneration to achieve hearing restoration.

Our proposal has two aims. The first is to use drug-like components to achieve reprogramming and hair cell regeneration in a large animal (pig) model. The use of drug-like molecules (small molecule compounds and siRNA) makes it possible to translate our work into clinical application, as the genetic manipulation we used in mice is not suited to humans. The use of the pig as a model system is a major step forward translating our work to the clinic. The pig inner ear is developmentally similar to the human inner ear, as both are fully developed at the embryonic stage. The hearing profile in the pig overlaps with human hearing range. A pig inner ear is virtually anatomically identical to a human inner ear, with a similar size, making it ideal for developing a surgical procedure that optimizes the route of inner ear delivery. Success of the study will help us to move the work from animal models to humans.

Our second goal is to evaluate a U.S. Food and Drug Administration (FDA)-approved drug for treatment of NIHL. We have recently identified a pathway that plays an important role as treatment for NIHL. We have obtained compelling evidence in mice that the drug is potent for promoting hair cells against noise-induced damages, to maintain the hair cell-to-neuron connections, and to protect against NIHL. We will use the pig model to study the efficacy for the drug-mediated protection against NIHL and repair of synapses after noise exposure.

Combined, our study will advance the work of hair cell regeneration using drug-like molecules in the pig inner ear, bringing hair cell regeneration a major step forward to potential clinical application. After the successful assessment of the FDA drug in the treatment of NIHL in the pig models, we will be in a position to conduct a clinical trial in humans including in military Service Members who are exposed to noise/blast on a regular basis.