In this project, Professor Hannie Kremer at Radboud University Medical Center, Netherlands, develops a genetic therapy for people with a inherited form of progressive hearing loss.
Project start date: October 2022
Project end date: January 2026
About the project
Hearing loss in adults can be caused by environmental factors (such as noise) as well as by genetic factors. However, very few of these genetic factors are known.
Recently, a team of researchers led by Professor Hannie Kremer identified an inherited, progressive hearing loss called DFNA21. It is caused by a gene called RIPOR2: people with DFNA21 have a shorter version of the RIPOR2 gene and therefore produce a shortened RIPOR2 protein. In this project, the researchers aim to develop a genetic therapy to treat this kind of hearing loss.
How it works
Researchers will interfere with the production of the shortened RIPOR2 protein in the inner ear to see if they can prevent or delay the onset of hearing loss or its progression. To achieve this, they will design small synthetic compounds called antisense oligonucleotides (ASOs) that block the shortened RIPOR2 protein from being produced.
They will test these compounds in the lab and identify the ASOs which strongly reduce production of the shortened RIPOR2 protein. These will then be tested both in a mouse model of DFNA21 hearing loss and in stem cells from people with DFNA21, which have been turned into inner ear-like cells in the lab. This will allow the team to evaluate the efficacy and safety of these ASOs compounds.
How will this research benefit people at risk of 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.
If the work in this project is successful, the ASOs 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.
What we’ve learned so far
The researchers identified a set of antisense oligonucleotides (ASOs) capable of effectively preventing the production of the harmful RIPOR2 protein. In parallel, the team generated a patient‑derived stem cell line and used these cells to grow an early type of human inner ear precursor cells.
These cells were used to assess the effect of the ASOs in the most relevant cell model for the human inner ear that we can grow in our lab. When testing the ASOs in mice, the researchers found that doses that are effective and that are used in other genetic therapies were toxic.
These findings highlight both the promise and the challenges of developing ASO‑based treatments for RIPOR2‑related hearing loss.
About the researcher
Professor Hannie Kremer is Professor of Molecular Otogenetics at Radboud University Medical Center, Netherlands. She was awarded an RNID Discovery Research Grant for this project in 2022.
Hearing is very important to stay connected with family, friends and colleagues, to enjoy music and to hear sounds of the environment for example while walking in the woods. My motivation is that my research can contribute to prevent or cure hearing loss in the future and for today, that my research provides answers to questions of people with regard to the cause of their hearing loss or of the hearing loss of their child.”
