St. Jude Children’s Research Hospital investigators regenerated auditory hair cells in adult mice using genetic manipulation. This research provides possible advanced treatment for auditory loss in humans.
The leading cause of hearing loss is due to auditory hair cell depletion. It could be caused by a variety of reasons such as loud noise, accidents, illness, aging or medications. Some of the childhood cancer survivors are also at risk due to chemotherapy agents.
Treatments has focused on electronic devices like hearing aids or cochlear implants, because auditory hair cells do not grow back once lost.
Tackling hearing loss with gene expression:
Unlike in humans, auditory hair cells do not regrow in fish and chicken. The process involves down regulating expression of the protein p27 and up- regulating the expression of the protein Atoh1. This was similarly attempted in bred mice.
By manipulating same genes, researchers induced supporting cells located in the inner ear of adult mice to look like immature hair cells and to begin producing some of the signature proteins of hair cells.
Researchers also identified the genetic pathway for hair cell regeneration and explained how proteins in that pathway cooperate to substitute the process. The pathway included the proteins GATA3 and POU4F3 along with p27 and ATOH1. Investigators found that POU4F3 alone was sufficient to regenerate hair cells. When both ATOH1 and POU4F3 were involved, more hair cells were regenerated.
The study suggests that patients may benefit from therapies that target the proteins identified in this study. These findings have implications for a phase 1 clinical trial that utilizes gene therapy to restart the expression of ATOH1 to regenerate hair cells for treatment of hair loss.
The transcription factor needed for hair cell development is ATOH1. In humans and other mammals, the gene is switched off when the process is complete. In humans, ATOH1 production stops before birth.
The study suggests that targeting p27, GATA3 and POU4F3 may enhance the results of gene therapy and other methods that aim to restart the ATOH1 expression.
This research also revealed a novel role of p27. This protein is best known to check cell proliferation. However, in this study, p27 suppressed GATA3 production. Since GATA3 and ATOH1 work together to increase expression of POU4F, decreasing GATA3 levels also reduced expression of POU4F. When the p27 gene was deleted in mice, GATA3 levels increased along with the expression of POU4F3. Hair cell regeneration also increased.
Further works to identify other factors, including small molecules, that are necessary not only to promote the maturation and survival of the newly generated hair cells but also to increase their number.