Alain Dabdoub

Moving Beyond Wnt and Notch Pathways for Hair Cell Regeneration

By Christopher Geissler, Ph.D.

There are several active human clinical trials evaluating the safety of inner ear hair cell regeneration therapies, but these therapies’ target mechanisms may be insufficient to stimulate hair cell growth in the adult mammalian cochlea. These approaches rely on the canonical Wnt and Notch signaling pathways and the Atoh1 molecule, which is necessary for hair cell regeneration and is regulated by these pathways. 

However, a report published in Molecular Therapy in May 2019 by Anshula Samarajeewa, Bonnie E. Jacques, Ph.D., and Alain Dabdoub, Ph.D., a member of Hearing Health Foundation (HHF)’s Hearing Restoration Project (HRP) consortium, notes that there has been very limited success thus far in regenerating hair cells in adult mammalian cochlea using these signaling pathways. This likely means, the authors write, that researchers will need combined approaches that also use epigenome-editing techniques to address changes to the genetic material and activity that occurs with age. 

Both the Wnt and Notch pathways play a role in determining how inner ear cells develop into specific types of cells and multiply, and they are also important in the development of the cochlea as a whole. Activating Wnt pathways and inhibiting Notch pathways can turn supporting cells into hair cells in fetuses and newborn mammals, making these key targets for hair cell regeneration. But both become much less effective as the body ages. Manipulating these pathways in adult animals has led to some success in regenerating hair cells, but these new hair cells tend not to develop fully, do not form necessary connections with auditory neurons, or even survive.  

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This lack of success is not because these pathways no longer exist in adults; researchers have found that they are still functional. This suggests that there are epigenetic changes that occur as a result of aging to make the adult cochlea less receptive to regeneration. Targeting epigenetic enzymes in addition to the Wnt and Notch signaling pathways may therefore prove more successful, but researchers still need to determine which part of the chromosome to target. This process would involve gene-editing techniques like CRISPR. This type of epigenome editing has slowed hearing loss in newborn mice, but it has yet to be tried in adult mice. If successful, this technique has the potential to treat hereditary and acquired forms of hearing loss.

HRP consortium member Alain Dabdoub, Ph.D., is a senior scientist, biological sciences at Sunnybrook Research Institute, University of Toronto. For more, see hhf.org/hrp.

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