Research into Usher syndrome
Research into Usher syndrome
If you had to choose between being deaf or blind, what would your choice be? People with Usher syndrome do not have this choice, because they become both. This progressive loss of two of our most important senses has an enormous impact on the quality of life of affected individuals. But what causes Usher syndrome?
Usher syndrome is a rare hereditary condition caused by small DNA errors in so far 11 different genes, also called mutations. The 11 genes that contain errors that lead to Usher syndrome each contain the code for the production of a different protein. The protein-coding parts of genes are called "exons”. Proteins are the workhorses of the cell and their function is determined by their 3D folding. Most proteins are made up of different domains, each of which is folded in a specific way and which fulfills its own function within the total protein. The vast majority of mutations that lead to Usher syndrome lie in the protein-coding regions, the exons, of the genes. Such a mutation can disrupt the folding of (domains). in) alter the protein in such a way that its function is affected, which then leads to a disease such as Usher syndrome.
The hearing loss seen in people with Usher syndrome can be compensated for by the use of hearing aids or cochlear implants. The loss of vision is still untreatable. However, in recent years, researchers at Radboud university medical center have developed a promising therapeutic strategy for Usher syndrome: exon skipping, by using antisense oligonucleotides (AON), also called "genetic patches". AONs are molecules that are designed in such a way that they can bind to specific exons in which disease-causing mutations occur in patients. These exons are therefore made invisible to the protein translation machine in the cell. If an AON is chosen correctly, it can mask the region in which a pathogenic mutation is located, causing the protein product to become slightly shorter but still functional.
However, Usher syndrome is extremely heterogeneous, which means that researchers know of more than 2000 causal mutations for which different AONs could be developed, the ultimate example of personalized medicine. Identifying the correct exons to skip and producing a functional AON is therefore time-consuming and expensive. In this project, the researchers want to develop a method that accelerates and improves this process and allows them to accurately predict a possible exon skipping therapy based on the identified hereditary errors.
Unique to our project is the combination of the use of artificial intelligence and 3D predictions of protein structures. A computer can learn what a healthy protein looks like through a neural network. Using modern prediction techniques, they can also calculate the effect on the 3D structure of these proteins when an exon is skipped. The computer can then assess whether skipping a particular exon offers a good option for therapy. Because mutations that lead to Usher syndrome occur across the entire length of various proteins, this method can offer perspective for many patients who have not been treated until now.
The potential of this therapeutic strategy is therefore enormous, not only for the treatment of Usher syndrome, but for all hereditary disorders caused by mutations in genes that code for large proteins with a repetitive protein domain structure (such as Duchenne's disease and Spinal Muscular Atrophy).