Gene Therapy Strategies for Hearing Restoration
Abstract
Hearing loss is one of the most common consequences of combat injuries. It can be caused by blast-induced injury, such as those from improvised explosive devices (IEDs) as well as chronic over-exposure to noise. A recent study showed that 64% of wounded-in-action Service members returning from Iraq and Afghanistan have some form of hearing loss. Permanent hearing loss is often caused by death of sensory hair cells of the inner ear, and at present there are no therapies that can regenerate these cells. However, it has been known for 25 years that other vertebrates, such as birds, fish, and amphibians, are able to regenerate their lost hair cells spontaneously. These animals do so by mobilizing supporting cells that sit adjacent to sensory hair cells to divide and turn into new hair cells. As a result, a deafened bird is able to recover almost all its hearing in a matter of weeks or months. In contrast, when mammalian (and human) hair cells are killed, the surrounding supporting cells do not regenerate new hair cells. As a result, hearing loss is permanent. In this project, we will use animal models to develop and test experimental approaches for regenerating hair cells. In particular, our research focuses on three genes, Atoh1, Pou4f3, and Gfi1. These are transcription factors, or genetic switches, that are believed to be necessary for the formation of sensory hair cells. We will test the potential of these three factors to "reprogram" supporting cells into functional hair cells, both in genetically modified mice and by infusing cell-penetrating versions of these factors directly into the cochlea. The long-term goal of these studies is to develop gene or drug therapies that will promote sensory hair cell regeneration and treat deafness in injured Warfighters. However, we acknowledge that our proposal is based on animal models of deafness and is not likely to develop therapies that can be applied to humans in the short or even medium term. However, the field of hair cell regeneration is at such a rudimentary stage that the development of these animal models is necessary before any human work can be contemplated. Our work builds on seventeen years of experience we have accumulated in this field and proposes technologies that have not, to our knowledge, been developed by any other research groups. That said, the approaches we propose to develop will also be applicable to the civilian population if successful. Hearing loss in the general population can result from aging (where it affects at least 50% of retirees), exposure to environmental noise, or from chemotherapeutic drugs that kill hair cells. Although hearing loss is not life-threatening, it seriously impacts the quality of life, especially in seniors, and is a significant public health issue.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010715
Entities
People
- Andrew Groves
Organizations
- Baylor College of Medicine
- United States Army