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Final Report Summary - EYETN (Beyond the Genome; training the next generation of ophthalmic researchers)

Introduction; Eye research has often led the field in developing new ways to study and treat human diseases, especially in technology-driven areas like genetics, stem cell research and gene therapy. This is because human vision is our dominant sense and loss of it one of our greatest healthcare fears, ensuring that interest in eye research is high. EyeTN is a training network set up by some of the best vision research laboratories in Europe, in partnership with biotech companies working on genetics technologies or therapies for eye diseases, and co-ordinated from Leeds in the UK.

Project Objectives; In recent years the EyeTN partner laboratories and other ophthalmic researchers have made many remarkable discoveries about human vision and the causes of inherited retinal diseases (IRDs). However it is clear that, even using cutting edge technology, we are still missing many of the genetic variants that cause blindness. When we know the genes and proteins involved, we often do not understand how defects in them cause eye diseases; why there is so much variation in symptoms and severity; and why patients respond differently to treatment.

The EyeTN network was set up to address these questions through world-leading research. EyeTN projects formed a co-ordinated, collaborative programme of research into the causes of IRDs. They looked for new genes implicated in IRDs; new mutation classes undetected by conventional screening; and variants likely to influence the severity of IRDs. They studied the pathway regulating retinal vascular development, identified microRNAs that regulate gene expression in the retinal; and studied disease mechanisms. They also looked at response to known IRD therapies in patients and cellular models. These projects were carried out using state-of-the-art technologies, including stem cell and fish disease models, genomic and transcriptomic analyses and protein array technology.

At the same time the EyeTN network gave the next generation of European ophthalmic researchers unparalleled opportunities to train in some of the best inherited blindness research labs in the world. As well as carrying out academic research, the fellows trained with commercial partners and attended workshops on translating ideas/discoveries into therapies and commercially viable bioscience products. In this way EyeTN has trained a cohort of world class eye researchers who will continue support each other’s professional development and will ultimately become a collaborative research network for the future of eye research across the nations of Europe.

Work performed since the beginning of the project; The EyeTN network recruited 10 ESRs and one ER and successfully undertook 11 planned research projects across 4 work packages. The fellows benefitted from an extensive programme of formal teaching delivered with the help of our commercial partners. All fellows presented their work both at scientific conferences and to members of the public through social media and at public awareness events. Wherever possible fellows undertook secondments both in other research laboratories and in commercial partner laboratories. The network held 9 biannual supervisory board and sub-committee meetings, and culminated in an extremely successful and exciting final conference attended by both members and researchers from outside the network. Our EU-appointed external assessor stated that EyeTN looked set to achieve if not exceed all of its targets, a view shared by our external advisors (see below).

Main results so far; The current most widely used method for DNA screening finds ~60% of the genetic defects that cause IRD. Some of the remaining mutations are in genes not yet implicated in IRDs, but these are now rare, and an increasing proportion of the missing mutations prove to be in genes we know about but which are missed using current technologies.

Work package 1 tested different approaches to finding these mutations, as well as looking for new IRD genes. The WP1 fellows identified a series of large-scale structural variants and non-coding DNA changes near to or within known IRD genes that either cause or moderate severity of common forms of IRD. The effects of the non-coding variants were confirmed in Retinal pigment epithelium cells derived from patients’ stem cells. In addition, WP1 EyeTN researchers identified 5 new IRD genes.

Work package 2 studied families with eye diseases the severity of which varies from individual to individual, even though they carry the same genetic defect. This approach aims to dissect out other factors that influence severity. One fellow looked at levels of expression of IRD genes in human donor eyes, and found two that vary depending on the presence of nearby genetic variations. These are now being tested in families to see if they influences the severity of retinal disease. The other fellows in WP2 work on the extremely variable condition familial exudative vitreoretinopathy (FEVR), a defect of retinal vascular development. Together they identified 2 new genes involved in FEVR and studied the function of one. One of the fellows also screened DNA from other FEVR families and found a variant that may moderate severity, while the other carried out pilot work for a large scale screen for new components of the retinal vascular developmental regulatory pathway.

Work Package 3 used cellular and animal models to study the mechanisms by which mutations cause blindness in different forms of IRD. One project studied 2 microRNAs involved in regulating eye growth, looking at their expression and action and the effects of increasing or decreasing their levels in medaka fish embryos. The other WP3 fellow derived retina-like stem cells from the skin of patients with another eye disease, Retinitis pigmentosa (RP). In these he showed that this form of RP affects the primary cilia, making it one of a set of conditions known as ciliopathies. He then tested gene expression, determined which proteins this protein interacted with and studied a model of the disease in zebrafish.

Work Package 4 projects aimed to determine why therapies work in some patients but not others, and whether it might be possible to predict which. One project used a genetic approach, studying response to anti-VEGF therapy in large cohorts of patients with age-related macular dystrophy, a common cause of blindness in the elderly. This international collaboration identified several genetic variants that may predict treatment response. An experienced researcher working in a commercial setting took a protein-based approach to the same condition, finding several potential biomarkers of disease and of treatment response in patients’ blood. Another fellow made stem-cell derived cellular models of choroideraemia and used these to test possible therapies.

Expected results and Impact of the network; EyeTN research fellows have been involved in implicating 7 new genes in IRDs; found many non-coding and structural variants underlying IRDs; used cellular and fish models to determine mechanism in several blinding disorders; tested out several potential therapies; identified interacting proteins for one of the proteins involved in IRD; highlighted potential IRD modifier variants and found several biomarkers that appear to be associated to age-related macular dystrophy and response to treatment for it. This body of work has led to 19 peer-reviewed scientific papers so far, with many more submitted, in preparation or in planning. The work of our fellows has also been presented, often by the fellows themselves, at 52 national or international scientific meetings.

These findings have immediate translational value in improving genetic testing outcomes and giving clear risk information to patients and their families, as well as testing new therapies and providing new tools and methodologies. In addition the network has trained a cohort of the brightest and best researchers in vision and eye disease, to spearhead research in this important area within the EU in the future. All the EyeTN ESRs registered for PhD training in their respective centres. Two already successfully completed their PhD viva examinations, others are writing up and all are set to complete PhDs successfully. As they trained, EyeTN fellows disseminated their research via conference presentations and peer reviewed papers. In its 46th month the network held an exciting, informative two day conference open to IRD researchers from around the world, featuring talks from internationally renown retinal experts as well as EyeTN fellows and partners. The conference was live-streamed and talks are available as podcasts via the EyeTN website ( In addition, throughout their training the fellows engaged with the public through the EyeTN web site and twitter feed and presented at patient information days and science fairs in their host countries.

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