“The eye is the jewel of our body” Henry David Thoreau
Our eyes are the windows to the world. An incredibly sophisticated organ with a truly unique anatomy and physiology, the two million parts which comprise a single eye working in unison bestow us with our ability to see. One of our five senses, ‘sight’ is considered the most important in humans; facilitating the delivery of an estimated 36,000 bits of information every second to the brain making them accountable for an estimated 85% of our contact and impression of the environment. In terms of natural order, the importance of our eyes in placing ‘visual species’ like humans at the top of the food chain cannot be underestimated.
The sheer intricacy of this organ however means ocular pathology is a complex field. Deciphering the specific pathophysiological mechanisms of several diseases is incredibly difficult (as we will see), and as a result a great number of debilitating ocular diseases remain without an effective cure. Until the appropriate research is conducted, ocular diseases such as cataracts, glaucoma, age-related macular degeneration, diabetic retinopathy and dry-eye syndrome will continue to cause vision impairment, and in certain cases irreversible blindness, for up to 200 million people globally – a number steadily increasing due to the increase in aging populations. It is therefore imperative that therapies against the aforementioned ophthalmic pathologies are developed in order to alleviate the cumulative socio-economic and psychological impact these diseases could ultimately have on society.
How our NICB building would appear through eyes with distinct ocular pathologies
My research aims to address a part of this challenge, specifically by working on gene-therapy based therapeutic interventions for use in populations afflicted by destabilised or ‘leaky’ blood vessels characteristic of diabetic retinopathy. Our research group lead by Assoc. Prof. Phil Cummins, and based in the School of Biotechnology and National Institute for Cellular Biotechnology at Dublin City University, are undertaking this endeavour in conjunction with the Curtis group of Queens University Belfast, and the Ambati group of the Moran Eye Centre, UT, USA as part of US-Ireland R&D Partnership Program aimed at generating valuable discoveries and innovations leading to enhancements in health, disease prevention or healthcare.
A descriptive breakdown on diabetic retinopathy as put together by the OPGG of UCD and ICON Firecrest
This SFI-funded partnership is just one of many globally spanning ocular-orientated research networks within Ireland that I have come to know since branching into ophthalmic research. One research group I had encountered previously in my research travels was the Ocular Pharmacology and Genetics (OPGG) group based in the Conway Institute of Biomolecular and Biomedical Research of University College Dublin. Part of the 3D-NEONET consortium and boasting an impressive research track record in developing genetic and pharmacological treatments for human blindness, they as a group are equally adept in their outreach, dissemination, and promotion of ocular research within the research, patient and public audiences.
And so on a sun-scorched June 7th, I would find myself heading to the Conway Institute to attend the second bi-annual ‘New Frontiers in Ocular Therapeutics’ workshop run by the OPGG with support from Science Foundation Ireland and Bio-Sciences Ltd. Run over two days, this workshop was promoted as a gathering of those from all research backgrounds with an interest in developing eye therapeutics towards the clinic, and providing a forum to discuss their research, create new networks, and forge prospective collaborations.
The workshop did just that – a seventy strong cohort comprised of interdisciplinary experts, academics, clinicians, patient advocates, early career researchers, and PhD students, gathered together for what would be an excellent symposium in which any and all stakeholders in the field of vision research were represented and given an opportunity to discuss the state-of-play in ocular research, dissect approaches to modelling and therapeutic delivery, and perhaps an often missed opportunity at larger conferences – constructively network and engage with each other.
So as the sun was blinding outside, so began our assembly on all things to do with blindness. After a warm welcoming address from workshop coordinators and principal investigators within the OPGG of UCD; Prof. Brendan O’ Kennedy and Dr. Alison Reynolds, Dr. Sarah McLoughlin; Science Communications Officer of Retina International, gave an insightful overview of how patient advocacy has been a driving force for ocular research the world over. Incepted in 1978, the importance of Retinal International, and the 30+ patient led charities they coordinate with, to vision research over the last 40 years cannot be underestimated. To put some context, to hear their early efforts of uniting and informing patients, clinicians, researchers, policy makers and industry globally of the latest breakthroughs and discoveries in an era where the internet was not as readily accessible as it is today, was remarkable. Dr. McLoughlin’s talk particularly captured the tone of what this workshop embodies; in that having the opportunity to share experiences, learn from one another, and find ways to work together, ultimately leads to improvements to the needs of the patient community.
After that inspiring opener we were then ready to begin with the first of three thematic sessions; astutely organised to take us through the therapeutic pipeline – starting with the models and means of elucidating ocular pathologies, then to the development of delivery methods that overcome the nigh-impenetrable barriers that protect the eye, before finishing with aspects of translating scientific findings to innovative molecular therapies from bench to bedside.
Dr. Lasse Jensen (Linköping University and BioReperia) got us underway with his innovative approaches to modelling different phenotypes of diabetic retinopathy using the zebrafish model. Dr. Jensen presented convincing evidence for the use of the zebrafish over the oft-employed mouse as a translational model of human disease, and has used this to great effect in discovering new outcomes of anti-VEGF treatment of diabetic retinopathy of potential importance for improvement to treatments for the future.
Similarly, Dr. Tim Curtis (Queen’s University Belfast) reiterated the shortcomings of the aforementioned anti-VEGF therapeutic strategy, and presented his research groups findings examining the role of other pro-angiogenic factors in a diabetic retinopathy setting and gave a strong argument for their inclusion as therapeutic targets.
Prof. Yolanda Diebold Luque (University of Valladolid) then built upon the first two talks and reiterated in detail the importance in the choice in model for therapeutic development referring to the limitations of anti-VEGF treatments, with her talk covering how in vitro approaches have had to evolve to cope with the difficulties associated with acquiring and using human ocular tissue.
We then took a short break from in vitro and in vivo modelling, as Dr. Mark Mackey (Cresset) took us through in silico approach his company uses with which the biological activity of thousands of compounds can be determined for clients beforehand, with some interesting stories of drug reprofiling using said technique.
Dr. Natalie Hudson (Trinity College Dublin) then detailed her work on circadian clock components and their influence on the retinal function of mice. The circadian behaviour of proteins pertinent to retinal permeability was clearly highlighted with novel, unexplored therapeutic niches targeting endogenous proteins influenced by circadian rhythm as a therapeutic strategy looking incredibly promising.
Dr. Hanan Awad Alkozi (Ocupharm Diagnostics) then detailed her work looking at the therapeutic potential of a different endogenous protein; melatonin. Providing data from human subjects, Dr. Alkozi proposed that melatonin and its analogues offer great therapeutic potential in glaucoma treatment owing to its natural hypotensive properties.
To close the session, Mario Crespo Moral (University of Valladolid) continued with the melatonin theme in detailing his research elucidating the specific receptors and respective mechanisms that enable melatonin to induce a regenerative effect in the cornea using an ex vivo porcine model.
What was fascinating about this session was how it captured the diversity of approaches utilised in the ocular biology field. The importance of model selection was apparent as several existing therapies, such as anti-VEGF, are only partially effective in certain disease phenotypes; a limitation stemming from the models employed in their initial development. Human/pig/mouse/zebrafish, in vitro/in vivo/ex vivo/in silico; models within the ocular biology field are rapidly evolving, and the approaches on display in this session indicate, in certain cases, that the requisite for human tissue in order for effective research and development of therapeutics to be conducted could be a thing of the past.
After the lunch break/poster viewing we moved along the drug discovery pipeline from the theme of discovery to delivery as we examined the different innovative approaches being developed against specific pathologies.
Without a doubt, some of the greatest physiological barriers faced by pharmacologists are those located in the eye. Whilst topical treatment is the most convenient and by far the favoured means of delivery (the alternative involves frequent ocular exposure to sharp needles…), delivery is ultimately impeded by various naturally-occurring static and dynamic barriers, and efflux pumps, meaning any amount that happens to reach the area of interest is often not maintained at effective therapeutic doses for very long. This session aimed to cover the advanced research being conducted by some of the attendees in the area of method development for ocular therapeutic drug delivery systems.
Dr. Isabel Rodriguez Amado (International Iberian Nanotechnology Laboratory) got us underway detailing her work identifying naturally-occurring candidate molecules for functionalising drug-loaded nanoparticles to overcome the mucosal layer protecting the eye increasing latency and improving drug-delivery.
Dr. Laurence Fitzhenry (Waterford Institute of Technology) continued in this vein detailing his work on improving delivery of corticosteroids for dry-eye remedy. Employing a spectrum of innovative strategies, Dr. Fitzhenry demonstrated an impressive increased efficacy up to 50% for his formulations using ex vivo models as compared to a leading market competitor.
Prof. Rocio Herrero Vanrell (University Complutense Madrid) took us from the front of the eye to the back as she detailed how improvements in drug delivery strategies, such as biodegradable microspheres, have reduced the frequency of intraocular injections necessary for the treatment of a number of pathologies.
In a call-back to the first talk, Dr. Alison Reynolds (University College Dublin) spoke about her own experiences using the zebrafish model of proliferative diabetic retinopathy. Dr. Reynolds described how this model, along with other in vitro and ex vivo assays, were used in unison to screen small molecule libraries in order to identify novel anti-angiogenic compounds against the aforementioned disease.
Carlos Carpena (International Iberian Nanotechnology Laboratory) took us back to the issue of dry-eye but instead of looking at topical treatments, Carlos detailed his work on drug delivery via contact lenses. His in vivo work integrating dinucleotides into the matrix of the lenses effectively reduced dry-eye comparative to existing treatments presenting a novel platform for future therapeutic delivery.
Sergio Esteban-Pérez (University Complutense Madrid) closed the session discussing gene therapy strategies and his development of a hydrogel-based transfection agent for retinal pathologies. Sergio detailed the important aspects to consider when designing a topical agent and demonstrated effective GFP delivery and expression in vitro using an optimised formulation.
Targeted drug delivery to ocular tissues has been a major challenge for decades, however the coinciding of improvements to experimental modelling with the advent of nanotechnology, has driven development and advances in the area at a rapid pace over the last twenty years. Some of the work on display in this session really underlined how far therapeutic delivery has come in addressing the key limitations that have hindered efficacy until now, with a number of innovative, diverse approaches detailed. Certainly, the concept of a topical drop formulation that delivers a sustained release of a targeting therapeutic to replace invasive strategies currently in use for certain eye diseases does not look that far away from being a reality.
Before the day ended there was an opportunity for those interested to discuss European networking opportunities with key stakeholders of 3D NEONET, and experts in the UCD research office and Health Research Board, to explore potential opportunities for workshop attendees of all backgrounds to work together. This was once again an excellent opportunity as an early career researcher to sit at a table with some of the leading figures in their respective field and learn from their experiences in developing a profile, establishing networks, and securing funding at a European level.
The second day of the workshop got underway looking at the tail-end of the pipeline – translation from bench to bedside. Basic research, which furthers our understanding of the differences between ‘normal’ and ‘disease’ states, often does not directly translate in clinically useful applications. In relation to the ocular field, as iterated earlier, access to human ocular tissue for experimental purposes is quite restricted meaning the penultimate design of agents of therapeutics that achieve the highest efficacy with the minimal toxicity for use in humans, using non-human models in their development, is challenging. This final session aimed to look at how laboratory findings can be, and have been, integrated into clinical trials for translational benefit for patient populations.
Prof. Neil Lagali (Linköping University) focussed on the rise of hydrogel–based biomaterials as effective therapeutic platforms for ocular therapy, detailing the challenges associated with the development, testing, and obtaining of ethical/regulatory approval for conducting clinical investigations.
Dr. Ishbel MacDonald (MacDonald Regulatory Ltd) built on this talk by giving an overview, in the general sense, of considerations to be made when developing and bringing a concept for an ocular therapeutic from bench to bedside.
Dr. Rosemarie Carew (FIRECREST Solutions) then highlighted the importance of the design of a clinical trial in general – particularly from a personnel point of view. Dr. Carew then demoed a number of innovative digital strategies FIRECREST Solutions have deployed for a number of different trials across Europe that have proven efficacy in reducing trials costings, improving compliance, and increasing site/patient engagement.
Dr. Anne-Marie Bleau (Sylentis) then detailed her company’s experiences in bringing their RNAi-based drugs to market. In light of the content of the first three talks, the journey and successes of two different drugs from in vitro, to in vivo, to patient trials was eye-opening (pun intended).
Dr. Naomi Chadderton (Trinity College Dublin) detailed her experiences in contributing to a two-decade long research and development program at TCD that has used next-gen sequencing to improve the diagnosis, prognosis and understanding of a number of ocular diseases. This research has enabled a number of gene-based therapies to transition from a basic to translational setting, and in some instances even commercial.
The session finished with Kelly Mulfaul (Trinity College Dublin) who had an excellent opportunity to practise for her viva (scheduled the following week) by detailing some of her PhD findings which demonstrate TLR2’s role in oxidative stress and complement activation in translational models of age-related macular degeneration.
It is known that therapeutic development is time consuming (15 years average), expensive, and often met with low success – for every 500 therapeutic interventions which demonstrate positive outcome in animal models, there is one that might translate to humans. This success ratio is often lower for ocular therapeutics owing to the challenges herein. Learning the additional processes involved in taking an idea for an ocular therapy from basic to translational research was fascinating; the patient model and experimental protocols, the study designs and data evaluation, proper reporting – it was very informative to hear first-hand accounts of the impact these aspects had on a study outcome, for better and for worse.
The workshop then brought to a close with awards for posters for Alan Hibbitts of Royal College of Surgeons for his overview of an anti-fibrotic hydrogel designed to treat glaucoma patients, and Marina Zaki of University College Dublin for her work on the state-of-play of EU and FDA regulations for ocular therapeutics.
While this was one of the smallest conferences I’ve attended, it only strengthened my opinion that these intimate gatherings are more often than not the most worthwhile to attend. Attracting leading experts in the field from Brazil, USA, Portugal, Spain, and Sweden to name but a few, I not only got a chance to see them disseminate and discuss their highly impactful, innovative work which is leading ocular research today, but I got ample opportunity to discuss my work with them in great detail, exchange ideas and opinions, and forge new collaborative links for the future.
To give some perspective, this coming week I am presenting my work at XXIII Biennial Meeting of the International Society for Eye Research (ISER); one of the biggest eye and vision research meetings in the world, in Belfast, Northern Ireland. Whilst there, I have scheduled meet-ups with some of the attendees from the ‘New Frontiers in Ocular Therapeutics’ I got the opportunity to interact with at said meeting. In certain instances to discuss collaborations, in others to establish international networks – irrespective of the topic, they are opportunities I otherwise might not have had were it not for my attendance at, and more importantly the nature of, the workshop hosted by the organisers in UCD.
In closing, Prof. Kennedy and Dr. Reynolds, and all associated parties that made the workshop what it was, deserve big plaudits for what ultimately transpired to be an incredibly productive and enjoyable experience, and I would strongly recommend early career researchers target these types of meetings in their own respective fields. Such were the benefits, that in Dr. Reynold’s closing address in which she detailed the future of the workshop and suggested it may change from bi-annual to annual, I couldn’t help but find myself thinking ‘I hope so’.