Preventing and rescuing hearing loss

December 8, 2021

HSCI scientists identify role of protein behind rare Norrie disease

Microscopy image of hair cells.
Hair cells of the inner ear, which are affected in patients with Norrie disease. Credit: Edge Lab.


A team of Harvard Stem Cell Institute researchers at Mass Eye and Ear, led by Principal Faculty member Albert Edge, has identified the mechanism that can lead to deafness in the rare syndrome Norrie disease. The researchers found that the Norrie Disease Protein (NDP), which is lacking in patients with the rare disease, is essential for the maintenance and survival of hair cells, the cells in the ear’s cochlea that are responsible for hearing.

The researchers also found that a biological pathway believed to be vital for hair cell regeneration, known as the Wnt pathway, could mimic the effects of NDP by restoring hearing in deaf mice with Norrie disease. This method and another technique that overexpressed NDP in nearby cells were both able to prevent and rescue hearing loss.

The discoveries, published in the journal PNAS, may lead to promising treatment targets for the incurable disease and other forms of profound hearing loss.

Norrie disease is an inherited disorder caused by more than 100 different mutations in the NDP gene that can lead to blindness, deafness, and intellectual disability in males. While infants with Norrie disease are born blind, their hearing is typically normal at birth and progressively deteriorates to profound loss by an average age of 12 years. The hearing loss can be particularly devastating for the families with an affected child.

Previously, researchers had thought that blood vessel issues caused by Norrie disease are what led to vision and hearing loss. However, the new findings suggest a lack of NDP is what causes hair cells to deteriorate and ultimately leads to deafness.

By learning more about the role of this protein in hair cell loss, the researchers were able to target two pathways that effectively prevented and reversed hearing loss in mouse models with Norrie disease.

“Before, little had been understood about what causes children with Norrie disease to lose their hearing,” said Edge, a principal investigator in the Eaton-Peabody Laboratories at Mass Eye and Ear, and professor of Otolaryngology–Head and Neck Surgery at Harvard Medical School. “Through our research, we’ve identified potential pathways for future treatments to prevent the hearing loss. These findings may also have implications for more common forms of permanent hearing loss.”

New clues about a little-known condition

To better understand the role of the NDP gene, the researchers used knockout mice that lacked the gene. They found that these mice had abnormalities in their cochlear hair cells, which died between birth and 2 months of age, corresponding with the timeline of progressive deafness.

The researchers then tested two rescue models to restore hearing loss in the knockout mice. First, they stimulated the Wnt signaling pathway, which they had previously found to be important for hair cell regeneration. They did this by overexpressing a molecule called β-catenin in the newborn genetic knockout mouse, which replicated the effects of NDP on hair cells and resulted in normal hearing. This result points to the Wnt signaling pathway as one possible target for treatment.

The other method the researchers used was overexpressing NDP in cells adjacent to the hair cells, so that these supporting cells would secrete NDP into the area surrounding the hair cells. Once those cells secreted NDP, the protein bound to the hair cells, which restored normal function and rescued deafness in the mice.

“Those two methods respectively point to potential treatments that we are planning to the test in future studies,” said Yushi Hayashi, the research fellow who led the study.

Implications for other forms of hearing loss

Future studies will test potential treatments at different ages and disease stages in animal models. Gene therapy and other medications may be used as methodologies to stimulate hearing rescue.

The new findings can have implications for studying treatments for Norrie disease, which currently lacks a cure. Typically, Norrie disease is diagnosed when a child is born blind; thus, if a therapy for hearing loss in Norrie disease were available, it should be possible to initiate treatment before its onset.

The findings may also have implications for other forms of hearing loss caused by cochlear hair cell death. Currently there is no way to rescue and reverse hair cell death in humans. Edge and colleagues have been looking at other ways to spur the Wnt signaling pathway to regenerate hair cells and these findings may contribute to that work.

“There are a number of implications of this work, one that clearly NDP is a part of the overall picture of Wnt signaling in the normal ear,” said Edge. “While that work is very early and experimental, this new study strengthens our hypothesis that Wnt signaling is important for regenerating hair cells.”

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This story was adapted from a press release by Mass Eye and Ear, published on October 5, 2021.

Hayashi, Y. et al. (2021). Norrie disease protein is essential for cochlear hair cell maturation. PNAS. DOI: 10.1073/pnas.2106369118