Researchers may have brought us one step closer to gene therapy for the treatment of hearing loss, after discovering a way to regenerate auditory hair cells in mice.
It is estimated that about of adults in the United States have some form of hearing loss, with men being twice as likely to develop the condition than women.
Damage to the auditory hair cells is one of the leading causes of hearing loss.
Aging is a common risk factor for such damage, although the ailment can also arise through prolonged exposure to loud noise, injury (such as head trauma), ear infections, and other illnesses and diseases.
Auditory hair cells are the tiny sensory cells of the cochlea – the inner part of the ear – that enable us to hear.
These cells consist of hair-like projections, called stereocilia, that are responsible for transforming sound vibrations into electrical signals that are sent to the brain.
In humans, auditory hair cells are unable to regenerate in order to replace damaged ones. In fish and birds, however, these cells can regenerate.
“The process involves down-regulating expression of the protein p27 and up-regulating the expression of the protein ATOH1,” notes study co-author Jian Zuo, Ph.D., of the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital in San Francisco.
For their study – today in the journal Cell Reports – Zuo and team set out to determine whether they could trigger the same process in mice.
Using genetic manipulation
Using genetic manipulation, the researchers deleted the p27 protein and increased ATOH1 expression in mice.
When the mice experienced auditory hair cell damage as a result of exposure to loud noise, the researchers found that the cells supporting the auditory hair cells began to transform into auditory hair cells themselves.
Further investigation revealed that a number of proteins work together in order to regenerate auditory hair cells.
The researchers found that the deletion of p27 increased levels of a protein called GATA3 and boosted the expression of the POU4F3 protein. This increased ATOH1 expression, leading to auditory hair cell regeneration in the rodents.
The researchers explain that ATOH1 is a transcription factor required for the development of auditory hair cells. In humans, the production of ATOH1 stops in the womb.
According to Zuo and colleagues, however, their findings suggest that it may be possible to reactivate ATOH1 production in humans by genetically manipulating the p27, GATA3, and POU4F3 proteins.
“Work in other organs has shown that reprogramming cells is rarely accomplished by manipulating a single factor," said Zuo. "This study suggests that supporting cells in the cochlea are no exception and may benefit from therapies that target the proteins identified in this study."
The researchers said the findings have implications for a phase I clinical trial that is already under way elsewhere using gene therapy to reinstate ATOH1 production in humans.
The aim is to determine whether such a strategy can trigger auditory hair cell regeneration in humans, and whether this might be an effective treatment for hearing loss.
"Work continues to identify the other factors, including small molecules, necessary to not only promote the maturation and survival of the newly generated hair cells, but also increase their number," said Zuo.