Frequency 52%
208.000 patients
Gene name: USH2A (also known as: A930011D15Rik, A930037M10Rik, LOC269160, LOC381317, MUSH2A, Ush2a, Ushrn)
Gene size: 15.695 (bp)
Protein name: Usherin
Protein size: 5193 (aa)
There are 5 different transcripts known for this gene
TRIALS
There are currently a number of trials that may be relevant to patients with mutations in the USH2A-gene:RNA-therapy STELLAR exon 13
- Stem cell therapy jCyte
- Stem cell therapy Cedars-Sinai
- Medicine Ataluren
- Natural history study RUSH2A and CRUSH
- Medicine SLO-RP and NAC-ATTACK
NATURAL HISTORY STUDIES
The detailed mapping out of the natural history of the functioning of eyesight and hearing in the different types of Usher Syndrome is essential in order to be able to determine the effectiveness of future therapy. Only after studies have demonstrated the effectiveness and safety of certain therapy types, these will be made available to patients on a large scale after a long process of market implementation.
Two natural history studies have been started: the RUSH2A and the CRUSH study.
MEDICINE SLO-RP
In Australia, a clinical trial phase 1/2 was started with financial support from the Foundation Fighting Blindness
Nacuity Pharmaceuticals launched this trial under the name SLO-RP. The safety and effectiveness of the medicine NPI-001, an experimental antioxidant, will be tested in the coming two years. The medicine appears to be really promising for slowing down the deterioration of eyesight with people suffering from RP and Usher Syndrome, irrespective of which gene is defective or which mutations have taken place.
MEDICINE ATALUREN
In the laboratories of Kerstin Nagel-Wolfrum (Johannes Gutenberg Universität, Mainz, Germany) and Mariya Moosajee (UCL, London, UK) it was demonstrated that in cultivated cells of a patient with “nonsense” mutations in USH2A, about 20 to 25% of the normal quantity of USH2a protein is produced again after administration.
In London researchers wants to start testing the drug Ataluren in patients with Retinitis Pigmentosa as a result of “nonsense” mutations in USH2a and USH1c
REDUCE ER-STRESS
Westerfield and colleagues are busy testing various medicines against Parkinson’s disease and Alzheimer’s disease in their zebrafish models for Usher Syndrome. Expectations are that this will slow down the deterioration of the hearing and eyesight of the zebrafish.
RNA THERAPY @STELLAR
ProQR Therapeutics from Leiden, the Netherlands, treated the first patient with mutations in exon 13 of the USH2Agene with QR-421a in the phase 1/2 STELLAR trial on 11 March 2019. This STELLAR trial is based on the above-described study of Erwin van Wijk.
ANTISENSE OLIGONUCLEOTIDES EXON 13
Erwin van Wijk is researcher at the Radboudumc Nijmegen, the Netherlands, and studies the question whether the functionality of various artificial, short forms of the USH 2A protein (coded by so-called “mini-genes”) is sufficient to inhibit or even stop the deterioration of the eyesight.
DEVELOPMENT OF EXON EXCISION THERAPY
This study aims at permanently removing specific exons, which include hereditary mutations when patients are concerned, from the DNA of the photoreceptors in the retina and/or the hair cells of the inner ear with the help of the CRISPR/Cas9 gene editing technique.
GENTHERAPY MINI GENES
Erwin van Wijk is researcher at the Radboudumc Nijmegen, the Netherlands, and studies the question whether the functionality of various artificial, short forms of the USH 2A protein (coded by so-called “mini-genes”) is sufficient to inhibit or even stop the deterioration of the eyesight.
TESTING GENE THERAPY IN MINI-RETINA’S
The Stichting Ushersyndroom has funded a large part of the new research “Genetic drugs preventing blindness due to loss of USH2A function”. This investigation started at the end of 2021. The research team led by Jan Wijnholds, who works at the Leiden University Medical Center (LUMC), will test 2 treatment methods on ‘mini-retinas’ made from human stem cells. The researchers want to study whether the light-sensitive cells in the mini-retinas are expressed after gene therapy has been administered. Can the USH2a gene in the retina be replaced or is it also possible to repair the defective gene on the spot?
Use of non-viral plasmid vectors
prof. Mariya Moosajee from London (UK) will, with the help of the ‘Moon Rocket Grant’, conduct research into the “Use of non-viral plasmid vectors for Usher Syndrome”. She has developed a DNA plasmid for this purpose, which can contain the full-length USH2A DNA.
STEM CELL THERAPY
jCyte, is a company that has developed retinal progenitor cells (RPCs), a type of stem cell that only retinal cells can become. Clinical studies have shown that these cells can reach and even replace diseased retinal cells. The results of a phase 1 / 2a trial have shown that the treatment is safe and does not cause an immune response.
The Los Angeles-based Cedars-Sinai company has also received approval from the FDA to initiate a phase 1 / 2a clinical trial for patients with RP.
ROD-CONE THERAPY
Rod-cone therapy is independent of the gene and focused on treating the rods in the eye while keeping the cones intact. The rods of the retina die first (see light and dark).
INNOVATION
Also investigations and studies are conducted in the world that do not specifically offer a solution for people suffering from Usher Syndrome, but that may be of significance for them in the future. Solutions, therapies and medical aids for other disorders can in a later stage be applied to people suffering from Usher Syndrome as well.
REPAIR OF THE C.2299DELG MUTATION
Carla Fuster Garcia from Valencia, Spain, tries to repair faults/mutations in the USH2a gene with the help of the CRISPR/Cas9 system. Here she concentrates on the most frequently occurring mutation in the USH2a gene: c.2299delG.
UNRAVELLING THE DISEASE MECHANISM BY MEANS OF STEM CELL TECHNOLOGY
The lab of Anai Gonzalez Cordero of University College in London cultivates retinal organoids using cells coming from a USH 2A patient. Retinal organoids, also called ‘eyes in a culture dish’, are made from stem cells and they are used to get more insight into Usher Syndrome and to test the effects of various medicines. In connection with this, skin cells of a patient are re-programmed into stem cells and then developed further into specific body tissues, in this case a retina.
Do you want to know more about cultivating a retina from skin cells?
PSYCHO-SOCIAL STUDY
Usher Syndrome has major psycho-social consequences. The progression of the deterioration of two senses forms an ultimate challenge for the adaptability of people.
Professor Claes Möller from Sweden has done a lot of research into the life strategies of people suffering from Usher Syndrome, the psycho-social consequences and their well-being.
SLEEPING RESEARCH
Are patients suffering from Usher Syndrome so tired because of the huge efforts made in connection with their poor hearing and eyesight or is something else going on? Researchers in the Radboudumc try to find an answers to this question. There are indications that perhaps there is more going on, a genetic cause.
In summer of 2021, the research into ‘The recognition of sleeping problems with patients with the USH2A gene’ stared. Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) will finance a large part of this study.
THE CHALLENGES
There are many challenges in research into Usher syndrome. Researchers specifically focus on a methodology, a strategy and / or a specific Usher protein.
IT’S IN THE PROTEINS
The proteins control all processes in our bodies. These proteins are built using codes that have been captured in the DNA. Due to a writing error in the DNA a protein can be produced incorrectly or not at all. Fixing this DNA error changes the production of the protein and so makes the disorder disappear or reduces the symptoms. This is the idea behind the genetic therapies that are now under development throughout the world.
