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Ushering in New Therapies

A multidisciplinary group based in the Department of Otorhinolaryngology at Radboud University Nijmegen Medical Centre is forging new insights into potential treatments for Usher syndrome – one of the leading causes of deaf-blindness

A pioneering young scientist with a background in biochemistry and medical genetics, Dr Erwin van Wijk , discusses his research into personalised therapeutic interventions to treat a devastating hereditary disorder known as Usher syndrome

What sparked your interest in Usher syndrome (USH), a progressive genetic disorder leading to the complete loss of both vision and hearing?

I decided to study USH back in 2004 after my team and I discovered a novel isoform of the USH2A protein that was mutated in patients with the condition. Using a variety of proteomic tools – such as yeast two-hybrid and quantitative affinity purification – we effectively lifted the lid of Pandora’s Box and, excitingly, obtained novel insights into the pathogenic mechanisms underlying USH. Following the completion of my PhD in 2009, I obtained two personal research grants that enabled me to take my studies on USH to the next level – namely, the development of personalised therapeutic interventions for patients.

Are there details of your research project on USH2A -associated retina degeneration that you can share?

For my current project, I obtained a personal research grant from the Netherlands Organisation for Health Research and Development (ZonMW). This study is embedded in the Molecular Otogenetics research theme of Professor Dr Hannie Kremer, who is based in the Ear-Nose-Throat Department at Radboud University Nijmegen Medical Centre (Radboudumc). In addition, we were able to hire two PhD students who are currently working alongside us on the project.

This project is multidisciplinary, situated at the confluence of human genetics, ophthalmic research and neuroscience. Have you found the multidisciplinary approach beneficial to the project? How have you brought these disciplines together?

The research is conducted at the crossroads of three different departments in Radboudumc: Human Genetics, Ear-Nose-Throat and Ophthalmology. Our close proximity to each of these departments allows us access to expertise in each of these disciplines, which in turn enables us to combine clinics with molecular diagnosis and develop preclinical therapeutic strategies that can be evaluated in clinical trials. The multidisciplinary approach is therefore highly beneficial to the project, providing us with important insights.

How has the European young investigators network for USH (Eur-USH) aided your research endeavours?

The Eur-USH consortium consists of three major components: improvement of clinical and genetic diagnostics; deciphering molecular pathogenesis; and therapeutic development for the retina. In order for a therapeutic development to be successful, a combination of all three components is essential. Moreover, the six partners within the Eur-USH consortium are embedded in leading research institutes and groups, bringing together a unique set of complementary expertise. This has definitely helped to fuel my own research endeavours.

What challenges have you been presented with over the course of your study? Has the process of surmounting these obstacles provided you with any new research avenues?

In order to develop a successful therapeutic approach for hereditary disorders, two steps must be taken. First, it is essential to develop a therapeutic strategy, and second, it is important to have a model system that allows treatment efficiency to be monitored. Before we began our study, neither of these steps had been taken.

Additionally, USH2A is one of the largest known genes within the human body, with a coding sequence of 15.6 kb. Gene augmentation therapy with previously published adeno- associated viruses or lentiviral vectors is not an option as the USH2A coding sequence exceeds the cargo capacity of these vectors. Also, the current Ush2a knockout mouse only shows very mild signs of retinal degeneration at a later age. These challenges have inspired us to develop alternative therapeutic strategies and explore the suitability of other model organisms than mice for our study. Excitingly, our zebrafish model has proven to be extremely effective.

Can you summarise the project’s most significant achievements to date? Furthermore, what have been your personal highlights from this work?

This project has been particularly special to me because I have worked on it all the way from the initial identification of the gene to current therapeutic developments. As for the specific achievements themselves, the first has to be the generation of a zebrafish ush2a knockout. The second is the preclinical development of a promising antisense oligonucleotides-based therapy for a common intronic mutation in the USH2A gene, which results in the inclusion of a pseudo-exon that disturbs the open reading frame and leads to premature termination of the protein.