Study into the best approach of USH1B

Stichting Ushersyndroom (Dutch Usher Syndrome Foundation) announces with pride its financing of a study that will test the best approach for USH1B (gene) therapy by making use of, among others, patient-specific cell models and a large animal model. This may take a (gene) therapy for USH1B to the pre-clinical phase. Dr. Kerstin Nagel-Wolfrum, who works at the Johannes Gutenberg University in Mainz, will lead this project.

Children suffering from Usher Syndrome type 1 (USH1) are born deaf and with a non-functioning organ of balance (the vestibular system). The first signs of loss of eyesight, such as night-blindness and a decreasing field of vision, will present themselves later in the childhood period. USH1 is most often caused by mutations in the MYO7A gene (USH1B). About 14% of all people suffering from Usher Syndrome has type 1B. The MYO7A gene is a very large gene and the Myosin protein is also called a motor protein. Is has a ‘head and a tail’ and therefore it must be replaced or processed as a whole when developing a gene therapy.

New approaches
The large size of the MYO7A gene makes classical gene therapy using an AAV vector impossible. However, new approaches, including double and triple AAV vectors, mini-genes, prime editing, translational read-through and exon skipping, are promising new alternative therapeutic strategies. Please go to the Knowledge portal for further reading.

From skin biopsy to mini-retina
With the help of a skin biopsy from a USH1B patient (fibroblast), Dr Nagel-Wolfrum can further develop these molecular cells into a retinal pigment ephithelium (RPE) and a retinal organoid (RO). The retinal pigment epithelium is found between the retina and the choroid and it clears away the waste products of the rods and cones in the retina. The retinal organoids are also called the mini-retinas.

The possibility to model retinal disorders by means of fibroblasts into mini-retinas created unprecedented opportunities in the research area.

Gain insights and test therapies
By making use of the ‘mini-retinas’, Dr Kerstin Nagel-Wolfrum will gain more insight into the mechanism that damages the retina and causes loss of eyesight. Apart from this, she wants to subject these retinal organoids (mini-retinas) to various therapies in order to test them for their effectiveness and functionality. Dr Nagel-Wolfrum will also test the mini-genes by conducting an AAV vector-based gene therapy.

On to the pre-clinical phase
A large animal model, a USH1B pig, has already been developed and is ready for testing possible therapies. Dr Nagel-Wolfrum will apply the therapy that the pre-study with the retinal organoids (mini-retinas) has shown to be the most effective one when doing research on the pig model. This study is called the pre-clinical phase. If this pre-clinical phase leads to positive results, this can be promising for a possible therapy for patients.

In this project Dr Kerstin Nagel-Wolfrum closely cooperates with:

• U. Wolfrum (Institute for Molecular Physiology, JGU Mainz, Germany): USH1B pig model
• S. Gerber (University Medical Centre Mainz, Institute of Human Genetics, Germany): Bioinformatics
• M. Cheetham (UCL, London, United Kingdom): iPSC-RPE and iPSC-RO generation
• V. Kalatzis (Institute for Neurosciences of Montpellier, France): iPSC-RPE and iPSC-RO generation
• J. Gopalakrishnan (Heinrich-Heine University Düsseldorf, Germany): brain organoids

This project will have a duration of 1 year and has been budgeted at
€ 100.000, -. Stichting Ushersyndroom hopes that this study will contribute to the development of one or more effective treatments for people suffering from Usher Syndrome type 1B.

View the PowerPoint presentation about this research by Dr. Kerstin Nagel-Wolfrum