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Developing a gene therapy for DFNA21 hearing loss

This is a Discovery Research Grant awarded to Professor Hannie Kremer at Radboud University Medical Center, Netherlands, in 2022.


Hearing loss in adults can be caused by environmental factors such as noise but genetic factors also strongly contribute. However, very few of these genetic factors are known.

Recently, a team of researchers in the Netherlands, led by Professor Hannie Kremer, identified such a factor in several families where progressive hearing loss is inherited from generation to generation (a type of hearing loss termed DFNA21). They found that a very small part of a gene called RIPOR2 was missing, which leads to the production of a shortened RIPOR2 protein. Family members with hearing loss had the shortened version of the gene, and it is therefore likely that this underlies their hearing loss.

The team have estimated that about 30,000 people in Northwest Europe have this specific change in their RIPOR2 gene. These people are at risk of developing hearing loss or may already have hearing loss. Although hearing aids bring some benefit to people with this kind of hearing loss, they do not always work as desired, especially in noisy environments such as social events or work. Therefore, a therapy that prevents or delays the onset of hearing loss, or its progression, would be of major benefit for the many people with this genetic risk factor.


In this project, the researchers will start to develop a genetic therapy to treat DFNA21 hearing loss, which has a (usually) adult onset. They plan to interfere with the production of the shortened RIPOR2 protein in the inner ear to see if it can prevent or delay the onset of hearing loss or its progression. To achieve this, they will design small synthetic DNA-like compounds, called antisense oligonucleotides. These compounds block the shortened RIPOR2 gene from being used as a blueprint to produce the shortened RIPOR2 protein, preventing it from being produced.

They will first test these compounds in cells in the lab which produce either the normal RIPOR2 protein or the shortened version. Any of the tested compounds which strongly reduce production of the shortened RIPOR2 protein will be taken forward for further testing in a mouse model of DFNA21 hearing loss – these mice develop hearing loss in the same way that people with DFNA21 do.

They will also test the compounds in stem cells from people with the shortened RIPOR2 gene, which have been turned into inner ear-like cells in the lab. This will also allow the researchers to test for any unwanted side effects of the compounds, or effects on the activity of other genes.


If the work in this project is successful, the compounds will be taken forward for further development towards clinical trials and a treatment that could prevent hearing loss in people with this genetic risk factor. It will also provide a ‘proof of concept’ that this approach could be used to treat other forms of genetic hearing loss with adult onset.

Page last updated: 22 January 2024

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