Bringing the neuroprotective compound Norgestrel closer to the clinic (2013 -2016)
Professor Tom Cotter, University College Cork (Direct investment by Fighting Blindness)
Professor Cotter is the head of a large research group in Cork and he is a world expert in the area of apoptosis. This is the mechanism by how cells die and for the past number of years Tom and his team have been investigating the mechanism of photoreceptor cell death in retinal degenerations. Tom has demonstrated that the compound Norgestrel (the active compound of the oral contraceptive the “minipill” lends a protective effect to photoreceptor cells, preventing their death and therefore maintaining vision. This funding will allow the team to build on these encouraging results to develop this potential therapy towards a clinical trial.
Exploration of AAV-delivered gene therapies for LHON (2013-2016)
Professor Jane Farrar, Trinity College, Dublin (Joint Funding through MRCG/HRB 2012)
Lebers hereditary optic neuropathy (LHON) is a devastating mitochondrial disorder predominantly affecting the vision of young men for which there an unmet clinical need. Building on previous private funding, Jane’s team hopes to further optimise delivery of the mitochondrial gene Ndi1 in order to deliver energy back to the eye cells, restoring some useful vision. The initial results have assured that the gene delivery method is safe and well tolerated and the team is confident that this investment will help in their efforts to progress to the next stage of clinical development.
Target 5000 – Gateway to vision (2012– present date )
Target 5000 is the most ambitious project that Fighting Blindness has undertaken to date. The aim of Target 5000 is to identify every retinal disease causing gene mutation in the Irish population by DNA sequencing the estimated 5,000 Irish people believed to have a degenerative retinal condition. Target 5000 represents a vital and progressive step in facilitating the movement of laboratory research towards treatment. Click here for more information about Target 5000.
Gene therapy platform technology for dominant retinitis pigmentosa (2011- present date)
Genable Technologies Ltd
In November 2011 we announced the major breakthrough that Genable Technologies Ltd, a campus company set up by researchers at Trinity College Dublin, had secured €5 million in venture capital funding. This funding investment will enable the work to move into human clinical trials. The technology, known as suppression and replacement therapy, holds promise that a single injection into the eye will suppress the mutated, faulty gene and simultaneously replace it with a healthy version.
Exploration of the candidacy of RPE65 in the etiology of adRP with choroidal involvement (2011-2014)
Prof Peter Humphries, Trinity College Dublin (Joint Funding through MRCG / HRB 2011)
This project is focused on two families affected by autosomal dominant retinitis pigmentosa with choroidal involvement, having a mutation in the RPE65 gene. It is thought that the studies proposed in the project may reveal a new disease mechanism associated with RP and may also bear relevance to the design of future therapeutic strategies. A member of the family has received benefit from oral retinoid therapy currently in trial for treatment of the autosomal recessively inherited condition, LCA. Affected members of the family were reported in 2011 to possess a small sequence variation within the RPE65 gene which may render them amenable to such therapy and it is the purpose of this research to undertake further investigations into the molecular pathology of the disease in this family such as to obtain a clearer picture of the molecular basis for therapeutic benefit.
Cell therapies for treatment of diverse retinal disorders (2011-2014)
Prof Jane Farrar, Trinity College Dublin (Joint Funding through MRCG / HRB 2011)
Stem cell therapy holds great promise for the potential reconstruction of retinal tissue, where retinal degeneration is at an advanced stage. The aim of such treatments would be to replace cells that have died in later stage disease. However, in order for this promise to be realised, a source of transplantable photoreceptor precursors needs to become available and transplantation techniques need to be improved so that large quantities of cells can be persuaded to integrate functionally into degenerating retinas. This project is focused on addressing these areas in an effort to expedite potential treatments using this technique.
Previously Funded Projects
On the molecular pathology of retinal degradation caused by mutations within the IMPDH1 gene
Prof Peter Humphries, Trinity College Dublin (Joint funding through MRCG / HRB 2006)
The RP10 form of retinitis pigmentosa caused by mutations within the IMPDH1 gene is an aggressive, early onset condition which is responsible for around 5% of cased autosomal dominant disease. While this form of RP is very severe, the group has shown that a targeted disruption of the relevant gene gives a model demonstration showing virtually no disease pathology. The principle concept suggests that simultaneous co-suppression of both normal and mutant versions of the gene might convert a severe dominant retinopathy into a much milder form of disease, perhaps with few or minor symptoms, over the patient’s lifetime. This has been demonstrated in a murine model but the next step is to move into humans to see if similar affects can be achieved.
Gene therapy for Leber hereditary optic neuropathy using AAV2 to transfect the NDI1 gene
Prof Jane Farrar, Trinity College Dublin (privately funded)
LHON is a mitochondrially inherited disorder that can result in significant visual loss in patients. The mitochondria are the powerhouses of cells, and in LHON, this is compromised. The Trinity group are exploring ways of modulating or rescuing the symptoms associated with LHON in a mouse model of the disease by delivering a gene which in essence provides energy to the compromised cells in the eye.
AMD: validation in murine model of novel approaches to suppression of retinal neovascularisation
Prof Peter Humphries, Trinity College Dublin (supported by IAPB)
Current treatments for wet AMD treat the established disease. The approach developed in this project is pre-emptive and has been designed to intervene in early stage disease where the inner blood retina barrier is intact and impervious to systemically administered drugs. The group has developed a procedure for controlled, periodic, reversible modulation of the inner blood retina barrier which allows low molecular weight compounds to access the affected areas. There is huge potential for this as a minimally invasive systemic therapeutic modality for retinal disease, including RP and AMD, where, in early stage disease, the iBRB is intact and therefore impervious to systemically administered drugs.
Exploration of cell based therapies for retinal degenerations
Prof Jane Farrar, Trinity College Dublin (Joint Funding through MRCG / HRB 2007)
Stem cells hold great promise in the future treatment of a wide range of disorders, including inherited retinal degenerations, however, obtaining cells with the potential to repopulate particular tissues in the body is a big challenge. This project is working with microRNAs to influence the differentiation and development of cells and will measure and evaluate the effects on a mouse model. An increased understanding of the components involved in driving mammalian photoreceptor differentiation (such as microRNAs) may provide opportunities to develop methods which will in turn facilitate the generation of such cells in vitro and in vivo. Therefore, it is of interest to explore if miRNAs may be of value in driving photoreceptor differentiation.
Directing retinal precursor cells to become functionally integrated cone photoreceptors in host retinas
Dr Breandán Kennedy, University College Dublin (Joint funding through MRCG / HRB 2006)
This project, which finished during 2011 demonstrated the possibility of taking retinas from zebrafish and growing them in plastic dishes. These retinal “explant” cultures survived in vitro and could differentiate. The establishment of the technology meant that the group could identify factors that control eye development and to screen for drugs with therapeutic or toxic action in the eye. This technology will be used going forward in ocular drug discovery and development projects.
Other Projects Powered By Fighting Blindness
Prof. Paul Engel UCD
An interesting publication has arisen from an initial collaboration between Paul Engel’s group and that of Prof. Pete Humphries in Ocular Genetics at Trinity College Dublin. The TCD group had previously identified the gene for IMPDH1 as the site of the mutations that cause RP10, a particularly unpleasant version of RP that shows dominant negative inheritance, i.e. one needs only inherit the defective gene from one parent to go blind. The work in Prof. Humphries’ group in TCD strongly suggests that with RP10, having one copy of the enzyme (IMPDH1) is actually worse than having no copies at all! This suggests that the defective copy does active damage. The Engel laboratory have generated a model showing that defective IMPDH1 protein does not fold correctly, but also that it suppresses the correct protein folding of the normal unaffected enzyme. Understanding how this mutation affects the cell will ultimately aid drug design that will postpone or ideally prevent the loss of sight.
Prof. Pete Humphries, Prof. Jane Farrar and Dr. Paul Kenna, Trinity College Dublin
If you’re looking to find a fix, then first you need to understand what’s broken. In 1989 the Trinity College team was the first in the world to identify a mistake in a gene which results in the onset of RP (retinitis pigmentosa) – a condition which causes tunnel vision and affects thousands of people in Ireland alone. It was a landmark achievement in unravelling the genetic code. The team has now discovered how to ‘turn off’ the faulty gene and replace it with a new one. This therapy is delivered into the body within a harmless virus and it is hoped that clinical trials will begin within two years.
Stopping the cell killers, Apoptosis, Prof. Tom Cotter, University College Cork
Every day, millions of your body’s cells will die. And that’s exactly as it should be. In perfectly healthy people there is a controlled programme of cell death and replacement, in a process known as apoptosis. Disruption to this process results in diseases such as retinal degenerative disorders. The team is working to understand and manipulate this system to find a therapeutic approach to treating RP.
The Eye’s Iron Curtain, growth factors and the blood retinal barrier, Dr. Brenda Brankin & Prof. lan Stitt, UCD and Queen’s University Belfast
There’s a wall around the eye that lets the right nutrients in, and keeps everything else out. It’s known as the Blood Retinal Barrier (BRB). But in some eye diseases this barrier can break down with damaging consequences. This project is aimed at discovering why this occurs and how it can be prevented. The work has implications not just for degenerative eye conditions, but also eye conditions caused by diabetes.
A diet to save your vision, age-related macular degeneration: Mr. Stephen Beatty & Dr. John Nolan and Dr. Orla O’Donovan, Waterford Regional Hospital / Macular Pigment Lab WIT
The incidence of age related macular degeneration (AMD) has increased sharply in our aging population. Based on evidence that blue light can accelerate the progress of AMD, the team is studying a protective layer known as Macular Pigment (MP), which absorbs blue light. This pigment comes entirely from dietary sources. In the largest field study of its kind in the world, the Waterford team is monitoring 800 middle-aged healthy individuals taking dietary supplements, over a 10-year period measuring changes to the macula.
The bionic eye, retinal microchip implant: Mr. John Alderman, National Microelectronics Research Centre, Cork
The notion of the bionic man is a popular fiction. Now it is becoming reality with the retinal microchip implant. Normally, the photoreceptor cells of the retina convert light signals into electrical impulses, which are transmitted to the brain for interpretation. But in retinal degenerative diseases these cells die and the brain receives no signals. By using a microchip to replace the function of the dying cells, it is hoped to restore some vision even to those who have suffered complete sight loss.