By Andy Groves, Ph.D.
All vertebrates, except mammals, can naturally restore their hearing by regenerating lost hair cells. This is done by activating supporting cells to divide and transform into new hair cells following hearing loss.
Mammals including humans have supporting cells, but they cannot divide or produce hair cells in adult animals.
There has therefore been great interest in targeting mammalian supporting cells to try and regenerate hair cells. Hearing Health Foundation’s Hearing Restoration Project (HRP) has been studying the feasibility of gene therapy approaches to bring about the conversion of supporting cells into hair cells.
One of the challenges of delivering therapies to any part of the body, including the ear, is to make sure that the right cells get the right dose of the therapeutic compound, and to minimize the effects of the compound on other cells.
As part of the HRP’s Reprogramming and Gene Delivery Working Group, my lab, along with the lab of fellow HRP member Litao Tao, Ph.D., collaborated to design an approach to deliver gene therapies specifically to supporting cells of the ear.
In our paper in Hearing Research in March 2025, we identified a DNA “switch” (also called an enhancer) from a gene that is normally active in supporting cells but is not active in any other cells in the ear or the brain.
We built this switch into a gene therapy virus (an adeno-associated virus, or AAV) to see if it could switch genes on specifically in supporting cells when the gene therapy virus was delivered to the ear.
The team studied DNA near the gene Lunatic Fringe (Lfng), which is specific to inner ear supporting cells, and identified three potential "switches" (enhancers) that could activate genes in these cells. They inserted these switches into an adeno-associated virus (AAV) and injected it into newborn mice. The experiment demonstrated that the switches effectively activated genes exclusively in the ear's supporting cells, with no activity detected elsewhere. Credit: Seist et al./Hearing Research
We were pleased to see that the virus only activated its genetic cargo in supporting cells, and nowhere else in the ear or brain. Moreover, we found that the virus continued to produce its genetic cargo for weeks after we first introduced it to the ear.
Although this work is very preliminary, it shows that it is possible to design gene therapies for the ear that are carefully targeted at supporting cells. This is an essential first step in applying targeted gene therapies to treat hearing loss in humans.
HRP member Andy Groves, Ph.D. (left, above) is a professor and the Vivian L. Smith Endowed Chair in Neuroscience in the departments of neuroscience and molecular and human genetics at Baylor College of Medicine, and a 1996–1997 and 2012 Emerging Research Grants scientist. In April Groves will become the head of the department of developmental biology at Washington University School of Medicine in St. Louis.
Fellow HRP member Litao Tao, Ph.D. (left, below), is an assistant professor in the department of biomedical sciences at Creighton University School of Medicine.
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This research shows that it is possible to design gene therapies for the ear that are carefully targeted at supporting cells, an essential first step in applying targeted gene therapies to treat hearing loss in humans.