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      Improving therapies to regrow hair cells

      This work could, ultimately, lead to the development of gene therapies to restore natural hearing.

      This is a three-year project led by Dr Nicolas Daudet at the UCL Ear Institute. It started in March 2016 and will end in November 2018.

      Background

      Damage to and the death of the sensory hair cells in the inner ear is a leading cause of hearing loss.

      The only treatments we have are hearing aids and cochlear implants. Of course, they are both hugely beneficial, but they don’t restore natural hearing.

      Researchers around the world are trying to find ways to restore natural hearing through biological means. One way could be to use gene therapy to stimulate the regrowth of hair cells.

      A number of genes have been identified as important for the production of hair cells. These include Atoh1, a crucial ‘pro-hair cell’ gene, and Notch, which controls whole networks of genes. Notch is important in directing the production of hair cells and 'supporting' cells, so-called because they provide both structural and biological support to hair cells. In other species, such as birds, which can regrow lost hair cells, supporting cells can turn into hair cells and, importantly, replace themselves so that there is no net loss of cells in the cochlea. This doesn’t occur in mammals, which is why people who lose their hair cells experience permanent hearing loss.

      Current gene therapy approaches towards restoring hearing aim to stimulate the activity of Atoh1. But these approaches rely on turning supporting cells into hair cells – which depletes the number of supporting cells in the ear. Running out of supporting cells is likely to affect hearing. During development of the inner ear, hair cells and supporting cells both develop from the same precursor cell, which can turn into either hair cells or supporting cells, and also, crucially, can produce new cells to replace lost ones. Their production during development is known to be governed by Notch.

      So, there may be a better approach: to turn surviving supporting cells back into these precursor cells that can then give rise to both hair and supporting cells. But to do this, we need to understand more about the genes and processes involved, and to identify ‘pro-precursor’ genes to target with gene therapy.

      Project aims

      We're funding Nicolas and his team to study the effects of the Notch gene on other genes in the developing inner ear, to identify ‘pro-precursor’ genes. They will analyse how switching Notch activity on or off in developing chicken ears affects the activity of other genes in the inner ear. Using a variety of gene- sequencing techniques, they will identify genes which are activated – or switched off – in these situations.

      In a related project in their lab, the Ear Institute researchers have been looking at a gene called Lmx1a, which directs cells in the developing inner ear away from becoming hair cells or supporting cells. By comparing the genes affected by Lmx1a with those affected by Notch, Nicolas and his team will identify genes involved in governing the formation of the hair cell/supporting cell precursor. They will analyse the most promising genes further to uncover exactly how they are involved in this process, and to find out if they would be a good target for gene therapy.

      Benefit

      We believe Dr Daudet's identification of ‘pro-precursor’ genes could be important in a number of ways. It is still difficult to grow hair cells reliably in the lab, so increasing our knowledge of these genes could help scientists improve this. In the longer term, the genes he and his team identify could be used for gene therapies in people – if they are able to promote hair cell regeneration in cell cultures and animal models of deafness.