Trinity Team - Deciphering the causes of genetic eye diseases & designing innovative therapies
Genetic Causes:Inherited retinal degenerations (IRDs) are the most frequent cause of vision loss in people of working age, while age-related macular degeneration (AMD) and glaucoma are increasingly prevalent eye diseases, all greatly impact quality of life and health economics. The Trinity team characterized some of the first IRD genes globally and indeed is now at the forefront of genetic profiling of IRDs at a population scale using next generation sequencing (NGS) technologies. This research has resulted for the first time in defining the genetic architecture of these ocular disorders in Ireland. See Carrigan et al. 2015 British Journal of Ophthalmology; Carrigan et al. 2016 Scientific Reports; Farrar et al. 2017 Human Molecular Genetics; Doherty et al. Gene 2017, among others. This represents extremely valuable diagnostic information for patients and is essential to enable targeting of therapies to the right patients in the future.
Innovative Therapeutics:A key goal is to develop novel interventions to treat blindness. The challenge is significant with more than 300 IRD genes and many genetic risk factors for AMD and glaucoma. In addition, within individual genes many different mutations can cause disease; families can have a unique personalized mutation. The team has investigated the molecular causes of IRDs and has explored novel therapies addressing critical problems such as the immense genetic heterogeneity inherent in IRDs with innovative technologies. See Chadderton et al. 2013, European Journal of Human Genetics; Trapani et al. 2014, EMBO Mol Medicine; Farrar et al. 2014, Visual Neuroscience; Palfi et al. 2015, Molecular Therapy Methods Clin Dev; Mansergh et al. 2015, Molecular Vision; Palfi et al. 2016, Scientific Reports; Geoghegan et al. 2017, Oncology Letters; Hanlon et al. 2017, Frontiers Neuroscience, among others. Additionally, the team has developed a significant patent portfolio.
The genetic diversity in IRDs has been addressed in two ways:
- To circumvent mutations within a single gene, the team developed suppression & replacement technology, which was progressed via a TCD company, Genable Technologies and acquired by Spark Therapeutics (US). Exploiting a fundamental feature of the genome (degeneracy), the approach is applicable to other inherited diseases.
- Given the many genes involved in ocular disorders, it is unlikely that specific therapies will be generated for each gene. To address this, the team exploited secondary features common between ocular disorders enabling identification of novel targets with broad applicability. An initial focus has been mitochondrial (energy) deficiency; modulating mitochondrial function has resulted in benefit in disease models and new candidate therapies.
The Future:The team’s work has elegantly exemplified the power of genomics to provide an unparalleled understanding of the diversity of disease and the value of creativity to deliver innovative therapeutic solutions to circumvent such diversity. The focus now is on developing potent therapeutic approaches for IRDs, AMD and glaucoma by expanding collaborative networks, leveraging state-of-the-art know-how and expediting efficient translation of technologies. While the focus of the Trinity team is eye disease, significant genetic diversity underpins many other human disorders. Hence an additional objective of the team is to help drive the medical genomics agenda in Ireland, to aid in providing improved diagnoses, prognoses and therapeutic options for patients with inherited disorders.
Current Trinity Team & Funders:Sophia Millington-Ward, Naomi Chadderton, Arpad Palfi, Adrian Dockery, Daniel Maloney, Ciara Shortall, Laura Finnegan, Laura Whelan, Adlet Yesmambetov, Ruth Kelly, Marian Humphries, Sophie Kiang, Paul Kenna, Pete Humphries, Jane Farrar.
The research of the Trinity team is supported by awards from Science Foundation Ireland (SFI), Fighting Blindness Ireland, The Health Research Board of Ireland, The Medical Research Charities Group, the Irish Research Council, the European Research Council, EU Framework and Marie Curie programmes.