Researchers identify mechanism that can lead to deafness in rare Norrie disease
A team of Mass Eye and Ear Scientists led by Albert Edge, PhD, in collaboration with researcher Yushi Hayashi, MD, PhD, has identified the mechanism that can lead to deafness in the rare syndrome, Norrie’s disease. Researchers have found that the Norrie’s disease protein (NDP), which is lacking in patients with the rare disease, is essential for the maintenance and survival of hair cells in the cochlea, the cells responsible for hearing. .
They also found that a pathway considered vital for hair cell regeneration, known as the Wnt pathway, could mimic the effects of NDP in restoring hearing in deaf mice with Norrie syndrome. This method and another technique that overexpressed NDP in neighboring cells were both able to prevent and save hearing loss.
The new findings, published in the September 28 issue of PNAS, may lead to promising therapeutic targets for incurable disease and other forms of profound hearing loss.
Norrie’s disease is an inherited disease caused by over 100 different mutations in the NDP gene that can lead to blindness, deafness and intellectual disability in men. While infants with Norrie’s disease are born blind, their hearing is usually normal at birth and gradually deteriorates to profound loss around the average age of 12. Hearing loss can be particularly devastating for families with an affected child.
Previously, researchers believed that vascular problems caused by Norrie’s disease were responsible for the loss of vision and hearing. However, the new findings suggest that a lack of NPD is what causes the deterioration of hair cells and ultimately leads to deafness.
By learning more about the role of this protein in hair cell loss, researchers were able to target two pathways that effectively prevented and reversed hearing loss in mouse models with Norrie’s disease.
Previously, not much was known about the causes of hearing loss in children with Norrie’s disease. Through our research, we have identified potential avenues for future treatments to prevent hearing loss. These findings may also have implications for more common forms of permanent hearing loss. “
Dr Edge, Principal Investigator in the Eaton-Peabody Laboratories at Mass Eye and Ear, and Professor of Otolaryngology – Head and Neck Surgery at Harvard Medical School
Animal research reveals new clues to little-known disease
To better understand the role of the NDP gene, the researchers used knockout mice lacking the gene. They found that these mice had abnormalities in their cochlear hair cells, which died between birth and 2 months of age, corresponding to the course of progressive deafness over time.
The researchers then took a closer look at the pathology of the NPD knockout mice. By analyzing the expression of genes downstream of NDP, the researchers found that NDP controls a network of transcriptional regulators necessary for the maturation and maintenance of cochlear hair cells. They concluded that a lack of NPD affects the development of hair cells; hair cells appear normal at birth but as they mature some of them die and others have faulty protein expression. This could explain why children with the disease lose their hearing at an older age, sometimes as young as 7 years old.
After gaining a better understanding of the pathology, they tested two rescue models to restore hearing loss in knockout mice. First, they stimulated the Wnt signaling pathway that they had previously found important for hair cell regeneration. They did this by overexpressing a molecule called β-catenin in genetically modified newborn mice, which mimicked the effects of NDP on hair cells and resulted in normal hearing. This result indicates that the Wnt signaling pathway is a possible processing modality.
The other method they used was to overexpress NDP in cells adjacent to hair cells so that these supporting cells secrete NDP in the area surrounding the hair cells. Once these cells secreted NDP, the protein bound to hair cells, which restored normal function and saved deafness in mice.
“These two methods respectively indicate potential treatments that we plan to test in future studies,” said Dr Hayashi.
Implications for other forms of hearing loss
Future studies will test potential treatments at different ages and stages of disease in animal models. Gene therapy and other drugs can be used as methodologies to stimulate hearing rescue.
The new findings may have implications for studying treatments for Norrie’s disease, which currently has no cure. Usually, Norrie’s disease is diagnosed when a child is born blind; thus, if therapy for hearing loss in Norrie’s 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 resulting in the death of cochlear hair cells. Currently, there is no way to save and reverse hair cell death in humans. Dr Edge and his colleagues investigated other ways to stimulate the Wnt signaling pathway to regenerate hair cells and these findings may contribute to this work.
“There are a number of implications of this work, one that clearly NDP is part of the overall picture of Wnt signaling in normal ear,” said Dr. Edge. “Although this work is very early and experimental, this new study strengthens our hypothesis that Wnt signaling is important for hair cell regeneration.”