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RNA-THERAPY

The objective of RNA therapy, also called AON therapy, is to repair the genetic defect at RNA level, so that a smaller but partly functional Usher protein can be made.
For a specific mutation an antisense oligonucleotide can be designed.
Antisense-oligonucleotides, abbreviated by ASOs or AONs, can be regarded as a ‘genetic patch’ that covers the area of the mutation and makes it invisible.

In this way, the cause of Usher Syndrome is removed and, hopefully, the deterioration of eyesight (and possibly hearing) of this group of patients is stopped or possibly even improved.

THE GENETIC PATCH FOR USH 1C

Jennifer Lentz from New Orleans (LSU School of Medicine, USA) is working on a treatment for USH 1C patients who have a specific mutation in the USH 1C gene, the c.216G>A mutation. This mutation influences the pre-mRNA separation (See Splicing mutations in ‘From DNA to protein’). As a consequence of this mutation, a part of the USH 1C gene is not included in the mRNA. If this part of the USH 1C gene is missing in the mRNA, the production of the harmonin protein stops prematurely.

THE GENETIC PATCH FOR USH 2A

Zebrafishes turned out to be perfect models for studying the vision problems caused by mutations in Usher genes. Therefore, with the help of the CRISPR/Cas9 system a mutation (= small deletion) was made in exon 13 of the USH 2A gene of the zebrafish. The result of this was that these zebra fishes no longer produced USH 2A protein and that the eyesight of these fishes deteriorated.

TRIAL FOR EXON 13

ProQR Therapeutics from Leiden, the Netherlands, treated the first patient with mutations in exon 13 of the USH 2A gene with QR-421a in the phase 1/2 STELLAR trial on 11 March 2019. This STELLAR trial is based on the exon-skipping study of Erwin van Wijk.

The first results of STELLAR were announced in April 2020

EXON SKIPPING METHODOLOGY FOR USH1F

With the help of the ‘Moon Rocket Grant’ from Stichting Ushersyndroom is in 2022 the research of Monte Westerfield from Oregon (USA) and Erwin van Wijk (Radboudumc) to start. In this international collaboration they investigate the methodology of “Exon skipping as a future treatment for USH1F patients”.

VARIOUS NAMES

There are various names for therapy with antisense oligonucleotide:

AON therapy
ASO therapy
‘genetic patch’
RNA therapy

Dependent on the design an antisense oligonucleotide may have different functions. The ‘genetic patch’ can skip the stop coding (exon skipping) or correct the separation (splice correction). How is the “genetic patch” mutation- or exon-specific applied?

FROM DNA TO PROTEIN

The genetic material of every human is stored in our DNA. The DNA consists of many genes. Each gene contains the code for the production of a protein. Proteins are the building blocks of our body. Reading that code for the formation of a protein is a complicated process. How does this building plan work and where can things go wrong?

DUTCH CENTER FOR RNA THERAPEUTICS

Scientists and physicians of the Leiden University Medical Centre (LUMC) and the Radboudumc together started the Dutch Center for RNA Therapeutics (DCRT). This new virtual centre was set up with the objective to develop tailor-made RNA therapy. A therapy meant for patients with rare genetic disorders, such as Usher Syndrome.

A MEDICINE IN AN INJECTION

RNA therapy does not replace or repair a gene. AONs can be considered as a medicine. The therapy is reversible. When the therapy stops, there is no active substance left in the body.

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