Restoration of Inner Ear Cells in the Hearing Loss-Associated Human Inner Ear System
Abstract
Hearing loss (HL) is one of the most common forms of sensory deficits. Noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL) are common forms of HL that have a disproportionate effect on individuals in the military compared to the general population. In addition, patients with HL have higher levels of psychosocial stressors, including social isolation, anxiety, and personal and financial stress. Several factors contribute to HL, including genetic mutations, environmental factors (noise), and aging. Damage to and the loss of hair cells, the inner ear sensory cell that detect sounds, is the major cause of HL. Unfortunately, the human inner ear lacks the capacity to regenerate hair cells. Therefore, once these cells are damaged or lost there is no way for the body to replace them, making hearing loss a permanent situation. Although current therapies, such as hearing aids and cochlear implants, have improved hearing outcomes, they have significant limitations compared to normal acoustic hearing. As a result, there is a significant need for new therapeutic approaches that can restore hearing. In this proposal, we will examine two novel approaches to correct for genetic causes of HL and restore hearing. First, we will examine the use of genome-editing approaches to either correct specific HL-associated mutations or to silence the expression of specific genes. Second, we will use a novel, highly efficient approach (adeno-associated virus (AAV) to deliver gene therapy tools to augment the expression of HL-associated genes necessary for normal functioning of the hair cells of the inner ear. The ear is a particularly promising organ for genetic therapies since it is self-contained, relatively small, and easily accessible and therefore will not require invasive approaches for the delivery of genetic therapies. Although these approaches will be used to focus on mutations in two HL genes -- P2RX2 and TMPRSS3 -- that can cause NIHL and ARHL, the same genetic approaches can be more broadly applied to other forms and causes of HL both for military personnel and the general population, increasing the impact of this work. These potential genetic therapies will be tested in two complementary systems -- mouse models bearing human HL-associated genetic variants and human patient-derived stem cell differentiated into inner ear organoids. These complementary systems will allow us to assess the safety and effectiveness of genetic therapies in the restore of hearing in the mouse inner ear, as well as the impact of these treatments on the health, viability, and functionality of human hair cells. Given the lack of readily available tissue samples for the inner ear, these stem cell models provide one of the few approaches that can be used to study the deficits that give rise to HL, as well as the testing of potential therapeutic strategies in human tissues, an important step for the preclinical development of any potential treatment strategy. Testing these genetic therapies in mouse models of deafness and in human cell models of the inner ear are essential steps in the process of developing therapies that can be used for the clinical management and the correction/prevention of HL. It is expected that the results generated by this proposal will provide the necessary safety and efficacy data to begin clinical studies for the treatment of patients with HL. After the successful assessment of the U.S. Food and Drug Administration gene therapy in the treatment of NIHL, we will be in a position to conduct a clinical trial in humans including the military Service Members who are exposed to noise/blast on a regular basis. In fact, similar approaches to those being proposed in this application have already been implemented in early-stage clinical trials for several forms of blindness and spinal muscular atrophy. These genetic therapy approaches provide the opportunity for a single treatment to result in long-lasting/perma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310922
Entities
People
- Xue Liu
Organizations
- Leonard M. Miller School of Medicine
- United States Army