Gene Therapy Strategies for Hearing Restoration
Abstract
One of the most common causes of permanent hearing loss - including hearing loss incurred in combat - is the loss of hair cells in the cochlea that are responsible for detecting sound. One of the first genes to be switched on in newly-formed hair cells is the transcription factor Atoh1. Genetic experiments in mice have shown that Atoh1 is absolutely necessary for hair cells to develop, and that ectopic expression of Atoh1 in young mice can cause other cochlear cell types to differentiate into hair cells. However, in the past 5 years, several groups have shown that the efficiency of regeneration evoked by Atoh1 declines rapidly with age. However, recently published data suggests that two other transcription factors expressed in hair cells - Gfi1 and Pou4f3 - can cooperate with Atoh1 and improve its ability to activate hair cell genes in cell lines. We hypothesize that combination gene therapy with three transcription factors: Atoh1, Pou4f3 and Gfi1 will be significantly better at reprogramming supporting cells into hair cells than Atoh1 alone. The aims of the project seek to answer the following questions:1: Can Atoh1, Pou4f3 and Gfi1 reprogram supporting cells into hair cells in the acutely and chronically deafened cochlea? 2: Can infusion of cell-penetrating versions of Atoh1, Pou4f3 and Gfi1 reprogram supporting cells into hair cells in the acutely and chronically deafened cochlea? In the current reporting period, we have generated and bred cohorts of genetically modified mice to complete the first aim. We showed that activation of Atoh1, Pou4f3 andGfi1 in acutely and chronically deafened mice can indeed generate significant numbers of new hair cells. We have also optimized protein production methods for Aim 2.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2023
- Accession Number
- AD1229559
Entities
People
- Andrew K. Groves
Organizations
- Baylor College of Medicine