They hear well up to about forty years of age, but then suddenly deafness strikes people with DFNA9. The cells of the inner ear can no longer damage the damage caused by a genetic defect in their DNA. Researchers at Radboud university medical center have now developed a “genetic patch” for the type of hereditary deafness, which can eliminate the problems in the hearing cells. Further research in animals and humans is needed to bring the genetic domain to the clinic as a cure.
Hereditary deafness can manifest itself in a variety of ways. The hereditary defect (mutation) often causes deafness from birth. Sometimes, as with DFNA9, you will have your initial hearing problems after forty, fifty, sixty years. This is related to the way DFNA9 works mechanically. Everyone gets half of their genes from their father and the other half from their mother. If you have two healthy copies of the DFNA9 gene, your inner ear will function normally. If you get a copy of the gene from your father or mother, you become deaf later in life.
Spaghetti protein
Erik de Vrieze and Erwin van Wijk, both researchers at Hearing & Genes in the Ear, Nose and Throat department, have extensively studied the condition. De Vrieze: “We now know that you are actually extracting enough of the associated DFNA9 protein with just one healthy gene copy to be able to hear well for life. But there is a seizure in this condition.The mutated protein, in a way, interferes with the functioning of the healthy protein.It sticks to it, so that the healthy protein can no longer do its job.
This clumped protein spaghetti is always removed by the cells of the inner ear, but after decades the cleansing service in these cells reaches its peak and they can not handle it. those protein chunks more. Threshold value is exceeded. As a result, the waste accumulates, the hearing cells begin to function poorly and even die over time. After years of normal hearing, DFNA9 patients suddenly notice that their hearing is declining, and sometimes declining very rapidly. Until at some point they become deaf. “
Sufficient time for treatment
The specific DFNA9 mutation appears to have originated from a common ancestor in South Holland, somewhere in the late Middle Ages. This can be deduced more or less from the release of the relatively unique clinical demonstration, which is now estimated to occur in around 1500 people in the Netherlands (right) and Belgium. Perhaps even more important than the origin of the disease is whether anything can be done about it.
This condition has two favorable features for the development of treatment. First, it is a hereditary condition that only manifests itself after a few decades of life. In case effective treatment is available for this disease, there is a large enough schedule available to implement it before the hearing loss becomes real. “
Erwin van Wijk, Researcher
Inverting a mutant gene
The other point – developing an effective remedy – is a bit more complicated, but it offers good starting points. Van Wijk: “The idea is that by specifically deleting the mutated gene copy, you can prevent deafness. Without this mutated gene copy, mutant proteins will not be produced. Protein trimming will no longer occur. In addition, only one healthy gene copy will produce enough protein to maintain a good hearing. “
A genetic piece
De Vrieze and Van Wijk further developed this idea. Together with colleagues, they have now published the results of their research in the scientific journal Molecular Therapy – Nucleic Acids. “Genes, which live on our DNA, pass on the genetic code for the process of translation into proteins,” says De Vrieze. “To get from a gene to a protein, you will always need a process of translation through a so-called messenger RNA. And that’s just the process we focused on. The DNA error is specific in the gene DFNA9 can also be seen in the RNA.We developed a small piece of RNA that specifically binds to the messenger RNA derived from the mutated DFNA9 gene.As a result, the entire mutated messenger RNA is targeted for contamination. In this way, an essential link is lost and the mutant protein DFNA9 is no longer or hardened in. The RNA fragment we attach to the mutated DFNA9 messenger RNA is termed as oligonucleotide antisense or ” genetic patch “.
A view!
In the last few years, not only have De Vrieze and Van Wijk developed this genetic field, but they have also studied its effect on cultured cells. Their current article largely outlines these findings, as the approach works in cultured cells. So there is a “proof of concept”, as it is called in science. In short, the research shows that the approach works at the cellular level.
Arthur Robbesom from the “The Ninth of …” DFNA9 Foundation is thrilled with the study. “This provides a real insight into the approximately 1,500 people in the Netherlands and Belgium who suffer from this condition. “The foundation is also closely involved in this research. Robbesom:” Now it is important to take the next necessary steps in the research as soon as possible. We will give you our full support. “
Source:
Radboud University Medical Center
Magazine Reference:
de Vrieze, E., et al. (2021) oligonucleotide antisense-based contamination of c.151C> T mutant COCH transcripts associated with severely acquired DFNA9 hearing impairment. Molecular therapy: nuclear acid. doi.org/10.1016/j.omtn.2021.02.033.