Human Sensory Hair Cell Regeneration Using Direct Lineage Reprogramming: Toward a Regenerative Therapy for Hearing Loss
Abstract
A major barrier to hearing restoration research concerns the inaccessibility of inner ear hair cells deep in the temporal bone of the head, and their small numbers. Moreover, human inner ears are rarely available from biopsy. This makes experimentation to find drugs and therapies to restore hearing almost impossible. Additionally, current animal studies are unlikely to reflect the full effectiveness of potential drugs or gene therapy approaches for human use in this system. To overcome these problems, we have adopted a state-of-the-art direct lineage reprogramming strategy, to generate sensory hair cells in the laboratory, directly from readily available mouse and human cells. We show that reprogrammed human hair cells in culture have properties extremely similar to normal hair cells, including in morphological features and electrophysiological properties. This approach of direct lineage reprogramming promises to provide many new avenues for the future treatment of deafness and its causes, including: scalable means of rapidly generating cochlear hair cells to screen for additional genes and drugs able to induce hair cell regeneration; develop in vitro models of genetic disease using human hair cells; establish in vitro means to investigate mechanisms of human hair cell differentiation; and develop new gene therapy approaches to the problem of hair cell regeneration. We recently identified a cocktail of reprogramming factors that is able to reprogram mouse somatic cells into hair cell-like cells (induced hair cells) (Menendez et al., 2020). Our goal, and the aim of this research project, is to translate this approach to human cells. We propose to develop optimal reprogramming protocols able to efficiently induce bona fide sensory hair cells from readily accessible human somatic cells, with the goal of identifying factors needed to generate the various hair cell types. Producing this tool is the first step in accelerating translation of gene therapy approaches to hair cell regeneration to restore auditory function. Direct lineage reprogramming to grow human cochlear cells in large numbers, as proposed here, will allow immediate progression to a scalable, high-throughput platform for regeneration studies, including screening for genes and drugs/small molecules that can induce hair cell regeneration, thus providing a platform to test the many large drug libraries available, both through the National Institutes of Health and commercially. While our research is still in the discovery stage, as a future direction we anticipate testing bona fide samples of human biopsy material, to induce robust conversion of intact supporting cells into hair cells in the deafened ears. Drugs and gene therapy approaches discovered through this work will allow progression to preclinical animal testing, and subsequent clinical testing. Our long-term goal is to translate the first effective treatment to stimulate sensory hair cells in the deafened ears. Consistent with the stated goals of the Department of Defense Hearing Restoration Research Program, this is a novel area of research that has high potential for advancing therapeutic interventions to restore auditory function in Service Members, Veterans, and the American public living with auditory system disorders.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211009
Entities
People
- Andrew Mcmahon
Organizations
- United States Army
- University of Southern California