Research grants

of advanced retinal degeneration: a proof-of-concept study for RP

Project start date: 2023
Professor Majlinda Lako, Newcastle University

Thanks to a generous commitment from the AT Capital Charitable Foundation, Retina UK was able to conduct an additional grant round in 2022. The foundation committed to fully funding one project that would be relevant to the treatment of sight loss associated with mutations in the USH2A gene, and this project was successful after the usual peer review process.

Mutations in the USH2A gene cause Usher syndrome type 2 (USH2A), characterised by early bilateral hearing impairment and later onset of night blindness and visual loss. USH2A is the most common cause of deaf-blindness and the most frequent form of recessive Retinitis Pigmentosa (RP). The USH2A mutation spectrum is heterogeneous; moreover, the USH2A gene is too large to be packaged into gene therapy vectors.

A type of stem cells named “pluripotent” has shown promising outcomes with respect to generation of rods and cones, which transform light into electrical signals that can be processed by the brain. Pluripotent stem cells can be generated from each patient and guided to give rise to rods and cones; however, this process is time- and cost-demanding and does not allow for immediate availability of off-the-shelf ready-made cells for transplantation. Prof Lako’s proposed approach is to make the pluripotent stem cells invisible to the patient’s immune system (so called hypoimmunogenic) and then differentiate them into rods and cones, to be safely transplanted into anyone with RP (including RP caused by USH2A mutations) without the risk of immune rejection.

The researchers believe that this gene-agnostic hypoimmunogenic photoreceptor transplantation approach has far-reaching impact as it could benefit a large proportion of the RP community.

Project start date: 2023
Professor Jane Sowden, UCL Great Ormond Street Institute of Child Health

Professor Jane Sowden, from University College London’s (UCL) Great Ormond Street Institute of Child Health, will be tackling the challenge of restoring some vision at the later stages of sight loss. At advanced stages of retinitis pigmentosa (RP) and other inherited retinal conditions, most of the light sensitive cells (photoreceptors) across the retina have died. A potential route to restoring vision is to generate new photoreceptors from stem cells and place these at the back of the eye.

To this end, Professor Sowden and her team will micro-engineer a photoreceptor cell patch to implant into the retina, creating a tiny millimetre dimension scaffold for the new cells to sit in. They are hopeful that this scaffold will aid the survival and organisation of the implanted photoreceptors. Over the course of the project, they aim to demonstrate that the patch can successfully be surgically implanted in an animal eye; they will assess its compatibility with the living tissues around it and evaluate the behaviour of the new photoreceptor cells. This is a first step towards development of a therapy for late-stage RP that could be helpful in a large proportion of cases, regardless of the underlying genetic fault.

Project start date: 2023
Dr Jorn Lakowski, Southampton University

Project start date: 2023
Professor Jacqueline van der Spuy, UCL Institute of Ophthalmology

Professor Jacqueline van der Spuy at UCL’s Institute of Ophthalmology will work with collaborators in Germany and Turkey to delve into the consequences of toxic accumulation of a molecule called cGMP. The three year project will use cell-based models of a very severe form of Leber congenital amaurosis (LCA) caused by mutations in the AIPL1 gene (LCA type 4), but cGMP accumulation also occurs in a number of other inherited retinal conditions, so understanding how it contributes to cell death could have much wider relevance.

The team will use cutting-edge techniques to follow up on clues about how excess cGMP impacts vital molecular pathways, with the aim of finding targets for therapeutic intervention. They also aim to test whether a particular potential drug can dampen cGMP’s toxic effects. The drug compound has already been extensively refined in other laboratory work, and Prof van der Spuy hopes that her project’s use of highly sophisticated disease models, based on human cells, would allow for rapid progress into clinical trials in LCA4, should the drug show promise.

Project start date: 2023
Dr Roly Megaw, Edinburgh University

Retina UK and the Macular Society are co-funding a PhD studentship to investigate how particular mutations in the RPGR gene impact cone photoreceptors.

Different mutations in RPGR can cause either Retinitis Pigmentosa (which first affects the peripheral ‘rod’ photoreceptors and therefore our visual field and night vision) or a Cone Rod dystrophy (which first affects the macular ‘cone’ photoreceptors and therefore our central vision). Currently, we don’t know why these different mutations cause different symptoms.

Using cutting edge techniques in collaboration with scientists in Geneva, the team will mimic macular disease and investigate the mechanisms underlying cone damage. Finding out why different RPGR mutations cause different diseases could help identify future treatments, and could even provide a springboard for preventative therapies.

Project start date: 2023
Prof  Jacqueline van der Spuy, UCL Institute of Ophthalmology

Retina UK and the Macular Society are co-funding a PhD studentship to explore the use of prime editing to correct the most severe mutations causing Stargardt disease.

Prime editing is a cutting-edge technology in which a disease causing genetic change is precisely and permanently repaired in an individual’s genetic code, restoring the normal function of the gene. In this study, the researchers will investigate whether prime editing can efficiently correct one of the most common genetic changes causing Stargardt disease. By establishing methods for safely and precisely editing these particular faults, the project could contribute to the subsequent application of the technique across a huge range of conditions, potentially transforming future treatments for a wide proportion of those living with inherited sight loss.

This project is being co-funded by The Macular Society.

Project start date: 2023
Prof Omar Mahroo & Dr Matteo Rizzi, UCL Institute of Ophthalmology

Retina UK and the Macular Society are co-funding a PhD studentship. as part of a study to better understand how specific visual symptoms are linked to the diagnosis and prognosis of macular degeneration

We know how important it is for those living with inherited sight loss to feel that their experiences are understood by healthcare professionals. This project will provide clear evidence of the impact of certain disruptive and potentially distressing Stargardt disease symptoms that are typically under-recognised by ophthalmologists. Formal recognition of these symptoms will highlight the need for them to be discussed during appointments, ensuring that those living with Stargardt’s receive appropriate reassurance and support.

… and assess its efficacy in restoring RPE and photoreceptor function
Project start date: 2022
Professor Majlinda Lako, Newcastle University

A major form of RP is caused by defects in components of the “spliceosome”, an important and complex structure within cells. The spliceosome edits unwanted or nonsensical passages out of a set of genetic instructions so that only intelligible code remains for the cell to use. One of the most common causes of RP is a fault in a group of genes that regulate this process.

Thanks to earlier funding from Retina UK, Prof Lako and her team have used stem cell technology to generate retinal cells from patients with mutations in a key gene involved in the splicing process (PRPF31), and have demonstrated that retinal pigmented epithelial (RPE) cells and photoreceptors are affected at the structural and functional level.

The newly funded project aims to develop a PRPF31 gene therapy to increase levels of healthy PRPF31, and use the retinal cell model to assess the therapy’s efficacy in restoring RPE and photoreceptor function. This highly collaborative study, involving four institutions across the UK and Germany, provides a unique opportunity for rapid proof-of-concept, leading to the potential for rapid translation into a Phase I/II clinical trial for PRPF31 RP patients as an immediate outcome. Between them, faulty spliceosome genes are a relatively major cause of RP, so the outcomes of this project should also be applicable to the development of treatments for a wider proportion of our community.

Project start date: October 2020
Prof Robert MacLaren, Oxford University
This study is being funded in collaboration with the Macular Society

We are now supporting a PhD studentship at Oxford University, co-funded by the Macular Society, that will look into a potential new method for treating Stargardt disease and other conditions where “conventional” gene therapy may not be possible. Under the supervision of Prof Robert MacLaren, the student will investigate whether it is possible to use harmless viruses to carry special molecular tools into retinal cells in order to edit and correct the defective genetic code. Rather than targeting DNA, this technique will aim to edit a different molecule called RNA that copies and then carries the genetic instructions from the centre of the cell to the protein building machinery; the original DNA is hence left unaltered and safety may be improved.

• Read the six month project report PDF file | 127 KB (June 2021)
• Read the twelve month project report PDF file | 477 KB (December 2021)