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Molecular patch inhibits 'blindness' in human skin cells

A step closer to genetic therapy for Usher Syndrome

People suffering from the hereditary disorder Usher Syndrome slowly become both deaf and blind. Researchers of the Radboudumc in Nijmegen, the Netherlands, have succeeded in covering the hereditary defect with a genetic patch in the skin cells of a patient suffering from a specific type of Usher Syndrome. This brings a therapy for Usher Syndrome a step closer again.

Usher Syndrome is a genetic disorder which results in combined deaf-blindness in patients. The loss of hearing can partly be compensated by providing patients with hearing aids or a cochlear implant, but so far no treatment options exist to stop the deterioration of eyesight. Mistakes (mutations) in about ten different genes can lead to Usher Syndrome. More than half of all people suffering from Usher Syndrome have a mutation in the Usher Syndrome type 2a gene (USH2A).

Not an appropriate lorry

The development of gene replacement therapy for various inherited eye diseases (such as Leber congenital amaurosis and choroideremia) is strongly emerging, but not really appropriate for Usher Syndrome type 2a. Erwin van Wijk, geneticist at Radboudumc: 'These therapies are based on inserting a new, healthy copy of a defective gene in the appropriate eye cells. These copies are delivered by a molecular lorry, which in fact is a deactivated virus. This is technically not possible for  this type of Usher Syndrome. As a matter of fact, the USH2A gene is so big, that it does not fit in any of the currently available lorries. Therefore, we have to develop another strategy for the future treatment of these patients.'

Mistake in intron

Van Wijk and his colleagues have developed such a strategy. In order to be able to do this, they first had to know exactly what is going wrong within these patients. In 2012 it was discovered that a subset of Usher Syndrome type 2a patients the problem is caused by a mutation in an intron. Van Wijk focused his research on this group of patients. In order to be able to understand this research, it is important to explain the term ‘intron’. Proteins are the most important building blocks in all cells of our body. The DNA contains the code for producing these proteins. In the DNA, the code for a protein is not noted neatly in the right order, but in small pieces, the exons. In a manner of speaking, each exon contains a syllable of the complete word, a part with which the entire protein is built up. Exons are separated from each other by an intron, a piece of DNA that is not translated into protein.

Extra syllable

In normal human language, such an exon-intron-exon sequence could look as follows: pro-stpp-tein. The reading device in our cells reads the exon pro, skips the intron stpp and reads the exon tein and puts the two exons together to form protein. In case of Usher, the mutation in the intron causes an unpleasant situation: the first 'p' is changed into an 'o', resulting into pro-stop-tein. Now the reading device thinks that stop must be read as well and immediately obeys the command given by the word: it stops reading. In this way, the usable word protein is no longer formed.

Genetic patch

Van Wijk has developed a strategy to very accurately mask this additional syllable. This strategy is based on the use of an Antisense Oligonucleotide (AON). Van Wijk: 'We know the exact order of the letters of the mutated intron. We then make a molecular piece of text – an oligonucleotide – which seamlessly fits the mutated intron, so that it is no longer recognized as a part that also needs to be read. Actually, we use a genetic patch to cover the intron and make it invisible. In this way, we eliminate the cause of Usher Syndrome. We hope that this will offer us a way to stop the deterioration of the eyesight within this group of patients in the future.'

Treatment in sight?

In a publication in the journal Molecular Therapy – Nucleic Acids, Van Wijk and his colleagues show that this method works in the skin cells of a person suffering from Usher Syndrome with the mutation in the intron of the USH2A gene concerned. Van Wijk: 'Every cell in the body of the patient, so the skin cells as well, contain exactly the same genetic defect. This enables us to test the developed method in easy-accessible skin cells. We have now shown that it indeed works at the molecular level in skin cells derived from Usher Syndrome type 2A patients that have this specific mutation. This is a 'proof-of-concept', a proof that this approach is in theory possible. This is also the starting point for further testing this technology in zebrafish with the same genetic defect and in cultured light-sensitive eye cells of humans, enabling us to take the next step towards a treatment.'

Usher Syndrome Foundation

Ivonne Bressers of the Usher Syndrome Foundation: 'There never was any hope of a treatment for this large group of people suffering from Usher Syndrome type 2A. This breakthrough shows an important step in the development of a treatment and this makes the need for more money to finance the scientific research even more urgent.'


Molecular Therapy - Nucleic Acids: Antisense Oligonucleotide-based splice correction for USH2A-associated retina degeneration caused by a frequent deep-intronic mutation - Slijkerman R.W.N., Vaché C., Dona M., García-García G., Claustres M., Hetterschijt L., Peters T.A., Hartel B., Pennings R.J.E., Millan J.M., Aller E., Garanto A., Collin R.W.J., Kremer H., Roux A-F. and Van Wijk E.

The Usher Syndrome Foundation

Usher Syndrome Foundation is a foundation for and by people suffering from Usher Syndrome who want to commit themselves to generating more money for scientific research into a treatment.

The ambition of the Usher Syndrome Foundation is to be able to offer all people suffering from Usher Syndrome a treatment that will make their dream of not losing their hearing and eyesight come true by the year 2025.

Animation treatment of Usher Syndrome type 2A

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