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Research we are funding

We are currently funding a range of exciting projects and programmes, all of which aim to enhance our understanding of retinitis pigmentosa (RP) and related conditions, and inform the development of treatments for the estimated two million people affected worldwide.

Understanding the disease mechanisms and developing new therapies for RDH12-related Leber congenital amaurosis (LCA)
March 2018 – February 2021
LCA is the most severe form of early-onset retinal degeneration. This projects aims to increase knowledge of the molecular basis of this disease and accelerate development of an effective treatment. The team will develop new disease models, one using stem cells derived from a patient with LCA and one in zebrafish, so that both can be used to increase understanding of the effects of the disease-causing mutation in the RDH12 gene and test the potential of new drug and gene editing treatments.

Identification and functional characterisation of the missing ABCA4 variants in Stargardts Disease
July 2017 – June 2020
ABCA4 mutations affect the majority of people with recessive Stargardt disease and about 30% of those with con-rod dystrophy. This project aims to develop a cost-effective sequencing method for the entire ABCA4 gene, sequence 1,000 Stargardt’s cases worldwide and finalise a process for testing the effects of mutations. Ultimately the diagnosis of people with an ABCA4 mutation will be improved, and the identification of those suitable for participation in future clinical trials made easier.

Modelling effects of TIMP-3 mutations in RPE – insights into Sorsby disease and night blindness in retinal dystrophies
November 2017 – October 2020
This project aims to explore how changes in a protein called TIMP-3 damage the retinal pigment epithelium (RPE), leading to Sorsby Fundus dystrophy. The team will also look at whether gene editing technology might be a viable treatment for the condition.

Non-viral gene therapy using S/MAR vectors for Usher Syndrome
January 2018 – December 2020
This project explores an alternative to traditional gene therapy, which may have implications for a wide range of inherited retinal dystrophies, not just Usher syndrome. S/MAR vectors have the capacity to hold much larger genes, and they have no viral components. The team will explore whether this new approach represents a safe and effective future treatment option.

RPFB centre for the development of gene therapy for inherited retinal dystrophies – The Gene Team
August 2011 – February 2018
As a result of major advances over the last two decades, gene therapy for retinal disorders is now a realistic prospect. Professor Robin Ali’s team at the UCL Institute of Ophthalmology has been establishing the viability of this potential treatment. Their aim is to build a programme of clinical trials for various forms of retinal dystrophy, focusing in the first instance on those disorders for which there are the best proof-of-concept studies.
A state of the art adaptive optics (AO) imaging system at Moorfields Eye Hospital is being used to image the retina with an unparalleled degree of clarity and precision. The team continues to develop its pipeline of therapies and five ongoing ethically approved studies aim to clinically categorise patients in preparation for future trials. More than 40 publications have been generated by The Gene Team to date.
Take a look at the latest update from the Gene Team

Pharmacological therapies for Rhodopsin RP
March 2013 – July 2017
Inherited mutations in rhodopsin, the light sensing protein of rods cells, are the single most common case of autosomal dominant RP. Previous research conducted by Professor Mike Cheetham had identified a number of promising drug treatments which can delay photoreceptor degeneration and lead to improvements in photoreceptor function. His current project aims to advance pre-clinical development of these drugs, quantifying their efficacy and suitability for the various rhodopsin mutations present in the UK patient population. Ultimately, this study will facilitate the future translation of these promising pre-clinical findings to the clinic trials stage.
During this project Professor Cheetham’s team screened the effect of eight different drugs in animal models of rhodopsin RP. The team found that some of these drugs protected photoreceptor function and / or survival, some had no effect and others exacerbated RP symptoms. The team made a database of all the recorded UK rhodopsin sequence changes that cause RP, and then investigated the most common changes in cell models and showed that they can cause similar problems to the genetic fault they studied in the animals and responded positively to the best drugs. Therefore, the patients with these changes might be amenable to treatment with the same pharmacological mechanisms that were shown to be successful in the animals. Professor Cheetham’s team will now start building the case for a clinical trial to test the most successful compounds.

The development of human iPSC-derived ex vivo models of retinal degeneration and their analysis in splicing-factor RP.
April 2014 – May 2017
RP causes the degeneration of the retina due to events occurring within specialised and inaccessible retinal cells. A recent innovation allows the creation of stem cells from human skin and the transformation of these into retinal cells for use in the laboratory. Professor Webster’s team will use this technology to investigate cells from patients with certain forms of RP. Their discoveries will inform the development of future treatments for the condition.
The team have undertaken detailed analysis of a number of patient samples to identify the root genetic cause of the mechanisms by which the retinal cells are damaged. They have also investigated samples from carriers of a disease-causing mutation, some of whom show symptoms of RP and some of whom do not, in an attempt to identify why this might be.

Maintaining effective antioxidant capacity in a degenerating retina: a genetic approach to treatments in RP
August 2014 – July 2017
Gene therapy can restore function in many forms of RP, but it may not prevent further degeneration unless treatment begins early. The difficulty in slowing the degeneration of the retina could be because, while many genes can initiate the disease, the resulting abnormal retinal state can drive it forwards. Therefore, identifying the factors driving rather than initiating the degeneration could form the basis for useful future treatments. This project seeks to investigate antioxidant pathways within the retinal mitochondria as a step towards treating the oxidative stress which is a key factor in degeneration.
Professor Ali’s team were able to detect artificially produced changes in oxidative stress within retinal cells, and will apply the same measuring techniques to disease-induced changes. They are using these techniques to test the effects of intervention procedures, mainly small molecule antioxidants, as well as gene therapy approaches.

The RP Genome Project
November 2014 – October 2017
The RP Genome Project brought together the four largest research groups in the UK specialising in inherited retinal diseases (IRDs): The University of Leeds, London’s UCL Institute of Ophthalmology, Manchester Royal Eye Hospital and Oxford University Eye Hospital. It was the first project of its kind in terms of the level of collaborative working required for its success. Since then, three further sites have been added to the study, widening the scope for collaboration and the availability of data and resources. The new sites are in Southampton, Bristol and Cardiff.
The consortium has become a Genetics England Clinical Interpretation Partnership (GECIP) associated with the UK 100,000 Genome Project. This allows the team to ensure that ophthalmic genetics are well positioned among the 100,000 genomes being sampled and one of the consortium investigators has been chosen to lead the GECIP in the field of Ophthalmology. The consortium has had 17 papers published, with thirteen in proposal. The team has identified new disease-causing genes and mutations, finding the genetic basis for disease in more than 230 cases. It has continued to identify new patients for inclusion, with numbers now in excess of 200. It has received data back for, and completed analysis on, 346 samples and has identified five novel disease-causing genes.
Take a look at the latest update from the RP Genome Project

Supporting the triage of LCA patients for AIPL1-targeted gene therapy through functional validation of uncharacterised and novel AIPL1 variants
August 2015 – October 2017
Leber congenital amaurosis (LCA) has many similarities to RP and is characterised by severe loss of vision early in life. Led by Dr Jacqueline van der Spuy
UCL Institute of Ophthalmology in London, this project aims to identify which variations of a certain gene, AIPL1, are disease causing mutations.
The team has been able to establish conclusive evidence confirming the disease-causing status of AIPL1 variations detected in patients with Leber congenital amaurosis (LCA) recruited at Moorfields Eye Hospital. These findings are critical for supporting the accurate diagnosis and effective triage of LCA patients with these mutations.

This project was completed in October 2017.

DNA Damage as a Driver of Photoreceptor Loss in X-linked Retinitis Pigmentosa
November 2016 – October 2018
Mutation of the RP2 gene causes retinitis pigmentosa but the mechanism by which this happens is still not fully understood. Current data suggests that a reduced ability to deal with oxidative stress and DNA damage may be the issue, and this project aims to explore whether this is the underlying cause. It will also test whether drugs which target DNA repair pathways and/or antioxidant therapies represent a suitable treatment option.
The team has been able to demonstrate in vitro, loss of the RP2 gene does not impair a cells ability to detect DNA damage, however cells appear to be intrinsically more sensitive to DNA damaging agents. Data has been generated indicating that this may be due to disruption of a critical organelle in the cell known as the Golgi, which regulates the delivery of proteins to specific regions of the cell. Furthermore, the team has begun to test whether inhibitors of DNA-PKcs can restore Golgi function. Very preliminary data suggests that two DNA-PKcs inhibitors can restore Golgi morphology. Together, this data expands on a novel emerging role for DNA-PKcs in regulating Golgi function independent of its role in dealing with DNA damage, and provides a novel mechanism to account for defects observed in photoreceptors. Additionally, this provides a new avenue of research investigating if the inhibition of DNA-PKcs represents a novel strategy to slow or halt photoreceptor degeneration in RP patients.

Aberrant RNA processing in Retinal Dystrophies: understanding mechanisms and developing therapies
January 2017 – December 2019
Professor Mike Cheetham of the UCL Institute of Ophthalmology, London is leading a team researching Aberrant RNA processing in retinal dystrophies. This project is building upon previous research to better understand why gene mutations that might be tolerated elsewhere in the body can cause disease in the retina when this splicing process goes wrong. It is also testing potential treatments using stem cell technology.
Using an artificially produced retina the team discovered that photoreceptors maximise the information in their genes by splicing them together in complex ways to produce specialised proteins. This helps them to fulfil their highly complex function of detecting light, but it does make them more vulnerable to mutations. Sometimes they mistakenly splice in the wrong information, disrupting their function.

A method called RNAseq has been used to identify the complex splicing events and which parts of the genes the photoreceptors stick together during the process. The team has also identified the time window during which the splicing process occurs, and has produced stem cells with intentionally disrupted splicing factors to test whether they affect photoreceptor function. A number of individuals with potential splicing faults have been identified to study in more detail in the future.

The project is on track to reach its goals. It will continue until December 2019.

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