Pictured: Professor David Gamm, University of Wisconsin-Maddison & Dr. Laura Brady, Research Officer Fighting Blindness
Report by Laura Brady:
A host of leading international experts in vision research from Canada, USA, UK and Europe gathered in Dublin to participate in a series of knowledge exchange presentations and seminars for the prevention and treatment of retinal degenerations.
Retina 2016 was officially opened by Mary Mitchell O’Connor TD, Minister for Jobs, Enterprise and Innovation, who shared that the work of Fighting Blindness is “very personal” to her as she “has seen up close the challenges, difficulties and stresses faced by people who have lost their sight”. She noted that “many conferences are all about the experts, but Retina 2016 goes much further” and thanked Fighting Blindness for their consideration in including all stakeholders in this event.
Loretto O’Callaghan, Managing Director, Novartis Ireland emphasised the importance of partnering with the public and patients.
Kevin Whelan, CEO Fighting Blindness stressed that while researchers are working hard to secure the cure, it is “incumbent on Fighting Blindness to do justice to the people we represent by ensuring we are well positioned to ensure they have access to treatments and cures as they arise.”
The Scientific Programme began with an engaging presentation from Prof Andrew Lotery, University of Southampton, an expert Ophthalmology consultant who has been listed in The Times as one of the UK’s top 100 doctors. From his experiences in the clinic and with a specialty in medical retina, Prof Lotery provided examples cases of a frequently undiagnosed condition called Sorsbys Fundus Dystrophy. This is an early onset form of macular degeneration involving both a peripheral retinal dystrophy that can cause night blindness and a central retinal disease, similar to what is observed in age related macular degeneration (AMD). The genetic background of the disease resides in a mutation in the tissue inhibitor of metalloproteinase 3 (TIMP3) gene but the mechanism to how this mutation leads to disease is unknown. Prof Lotery discussed novel insights into the disease and described how exploring the pathology involved through genetic studies and induced pluripotent stem cells may also provide insights into retinitis pigmentosa (RP) and macular degeneration.
Prof Lotery cautioned that this condition may be more common than we think. He highlighted the necessity to genetically test idiopathic cohorts and in individuals who present with early onset AMD. Prof Lotery also described his experience of treating the neovascular, or wet, form of the disease using anti-VEGF injections and indicated many new approaches and innovations that may lead to future treatments of the disease.
Genes and gene therapy was the topic of discussion for the rest of the morning and we were delighted to welcome back to Ireland, researcher Dr Michael Redmond, National Eye Institute (NEI), United States. Dr Redmond received his PhD from University College Dublin before moving to the US where he and his team discovered RPE65, a complex protein that plays a critical role in the visual cycle process and is essential for normal vision. The mechanism by which this protein functions has been the primary focus of Dr Redmond’s research for a number of years. In his presentation, Dr Redmond described how his lab are using mouse models to determine the role of RPE65 in vision, particularly the minimum amount of chromophore required for cone photoreceptor structure and function preservation. Dr Redmond hopes that these studies will contribute to the application and management of RPE65 gene therapy trials and assist in assessing a beneficial therapeutic dose in human subjects, ensuring long term benefits.
Continuing the discussion on the role of RPE65, we heard from Spark Therapeutics, a US based company which has developed a gene therapy for a rare form of blindness known as Leber congenital amaurosis (LCA). Specifically, their therapy is for a particular form of LCA known as LCA2 that is caused by mutations in the RPE65 gene. Dr Daniel Chung, Ophthalmic Lead for Clinical Development at Spark Therapeutics discussed the design of a primary endpoint for a Phase 3 trial for inherited retinal degenerations. Spark Therapeutics were tasked with identifying a functional endpoint and then devising a technique by which improved functional vision could be captured following intervention. To achieve this, Spark Therapeutics developed the multi-luminance mobility test (MLMT), a mobility maze which encompasses aspects of visual field, visual acuity, light perception and contrast sensitivity. Results from the study demonstrated that following treatment, participants significantly improved their ability to navigate the maze course under very low light conditions, indicating an improvement in vision. Dr Chung also suggested that the MLMT holds the potential to be used as a tool in natural history and disease progression mapping.
We heard from genetic expert Prof Frans Cremers, Radbound University Nijmengen Medical Centre, Netherlands who illustrated the complexity in identifying causative gene mutations for inherited retinal conditions. To date, more than 250 genes are known to be associated with inherited vision loss but yet a likely disease-causing gene has only been established for only approximately 60% of patients. Therefore, for 40% of people living with an inherited retinal degeneration, a causative gene mutation cannot be currently identified. Prof Cremers emphasised the necessity to look more closely at the known genes for the unknown 40%, as many of the unidentified mutations may reside in the non-coding regions that represent 98% of the human genome.
Fighting Blindness funded researcher, Prof Jane Farrar, Trinity College Dublin described how we are now in a new era of gene discovery and diagnosis. She gave an overview of her role in characterising forms of retinal degeneration in the Irish population. She explained that genetic diagnosis is facilitating, when appropriate and with consent, moving people towards clinical trial. Prof Farrar also introduced exciting work her group has been performing towards the development of gene based medicines for two targets, autosomal dominant retinitis pigmentosa (RP) and mitochondrial related Leber Hereditary Optic Neuropathy (LHON).
Following on from previous discussions, Prof Elfride De Baere, University of Ghent, Belgium reiterated the theory that many of the unknown genetic variations in inherited retinal degenerations may be located in the non-coding regions of the genome.
The afternoon research presentations began with an insightful discussion on the applications and potential of cell therapy as a treatment for retinal degenerations. There are currently two major avenues for stem cell therapies – ‘preservation’ and ‘replacement’. To date, much of the focus has been on retinal pigment epithelium (RPE) cells because these are generated more easily and also more readily transplanted. Photoreceptor transplantation is a more difficult task because of the requirement for functional connectivity with nearby cells.
We were honoured to host Dr David Gamm, University of Wisconsin who shared with delegates his work on growing light-detecting cells using human pluripotent stem cells (hPSCs). His presentation eloquently highlighted the current state of this stem cell technology and its anticipated applications to the treatment of inherited retinal degenerative diseases. Dr Gamm described how his group has used this technology to grow human cells in a 3D environment that mimics the human retina. He emphasised that many things can be studied and determined in a dish and still have great impact and relevance to patients. For example, these models can be used to better understand the disease, test potential treatments such as gene therapy, gene editing or investigate drugs that may slow down a particular process. Dr Gamm’s work is an example of the many exciting developments which are now taking place in our understanding of the causes of retinal diseases and into their prevention.
It was a pleasure to welcome Prof Robin Ali, University College London, Chair of Fighting Blindness Medical and Scientific Advisory Board. Prof Ali gave an impressive overview of how his group has approached the task of trying to develop a photoreceptor cell replacement therapy for inherited retinal degenerations (IRD). Conditions such as IRDs, age-related macular degeneration (AMD) and diabetic retinopathies account for a large majority of visual impairments in developed countries. At the root of many of these conditions, is the loss of photoreceptor cells. Transplantation of just a small number of cone photoreceptors can have great clinical impact and accordingly, Prof Ali described his latest work on differentiating and transplanting embryonic stem cell derived cone photoreceptors in animal models. Prof Ali also addressed the many challenges researchers face in achieving successful photoreceptor transplantation.
Following on from this, we heard from Dr Shaomei Wang, Cedars-Sinai, Los Angeles who described the use of induced pluripotent neural stem cells as a strategy to preserve the remaining photoreceptors and protect the existing retinal anatomy and function. Dr Wang believes that stem cell therapy may offer a real hope to individuals affected by age-related macular degeneration and use of induced pluripotent stem cells represents a promising cell source for personalized therapies.
Moving away from the topic of cell therapy, Prof Bart Leroy, University of Ghent, Belgium presented an engaging clinical research perspective on his experience in the clinic. Prof Leroy described the genotypes and phenotypes in people who have bestrophinopathies and indicated how gene therapy could work for these conditions. Bestrophinopathies are a diverse group of conditions caused by either mono- or biallelic mutations in BEST1. Following the comparison of a number of different phenotypes, including current knowledge about mechanisms of the disease, it is suggested that a threshold of bestrophin protein production, blurring the differences between dominant or recessive mechanisms of disease, may be the main determinant of the phenotype.
Prof Austin Roorda, University of California described the fascinating work that he does to study structure and function in the eye using adaptive optics. Adaptive Optics is a technology that gives a sharp image of the living retina and allows us to see what is happening on a single cell basis. Its use is a crucial element in the fight to prevent, slow and cure eye disease in the retina. Prof Roorda also presented an interesting phenomenon whereby cones do not appear in confocoal AOSLO or in OCT images, yet retain function. This ‘dysflective cone’ phenotype is common to several retinal diseases and its identification may be important in identifying and selecting patients for treatments and monitoring progression of retinal disease.
As a patient organisation, it is crucially important to feature individuals who live with sight loss throughout the day.
Peter Ryan, Paralympic cyclist described eloquently his experience of losing his sight and the difficulty in learning to accept this. He reminded us all that while eyesight is far from a simple subject, day-to-day vision is a beautiful thing and the simplicity it gives a life cannot be measured in words.
John Delany, Senior Counselling Manager at Fighting Blindness expressed his admiration at the commitment, enthusiasm, optimism and determination of people to find answers to very difficult questions. John spoke on the importance of relationships and encouraged all clinicians, researchers and patients sitting in the audience to set about building connections and relationships that will make a difference in their quest to find cures and treatments for blindness.
Retina engages with Early Stage Researchers and Clinicians
The Retina Conference is a unique and fantastic platform for young minds to engage and interact with pioneering experts in the field of retinal research. Fighting Blindness is very committed to the exposure of early career researchers, clinicians and students. To facilitate this, social elements of the programme were designed to encourage the development and growth of new and existing relationships, both nationally and internationally. A ‘Breakfast with the Prof’ session offered a unique and informal setting to early career researchers and clinicians to speak with invited speakers on topics such as getting published, networking in science, connecting clinical practice with research as a clinician scientist and funding opportunities.
With over thirty posters (both scientific and clinical research) on display, many interesting discussions took place in the Exhibition Hall. Dr Sarah Roche, University College Cork was awarded the prize for ‘Best Poster’.
This year, three junior researchers were invited to give short talks and present their work to the international audience. Andrew Smith, University College Dublin (currently placed at the National Eye Institute in the US) was awarded the Geraldine Duggan Award for his presentation entitled ‘Identification and Characterisation of Cone Photoreceptor Enriched Factors in Zebrafish using CRISPR Cas92”.
The conference was closed by Christina Fasser, President of Retina International. Christina has been a leading voice in the effort to focus attention on the need for scientific research to find a cure or treatment for retinal blindness for over 25 years. She spoke about the importance of patients’ involvement in driving and leading clinical research and advocating for access to therapies when they become available.