Overcoming immune responses to retinal gene therapy: transforming the treatment of sight-threatening disease

Why is this research needed?

Gene therapy is currently being developed to treat a range of eye diseases including glaucoma, inherited retinal diseases, diabetic retinopathy, and age-related macular degeneration, which together affect over 1.3 million people in the UK.

The process involves delivering a missing or a protective gene directly into specific cells to treat a disorder. These therapeutic genes are inserted into their target cells using a vehicle called a “vector”. Typically, viruses are used as vectors because of their natural ability to deliver genetic material into cells, but they are first modified to remove their harmful properties before being repurposed as gene carriers.

Retinal gene therapy promises huge benefit to people who are living with, or who are at risk of sight-threatening disease, because the treatment could be administered as a single injection to last the whole of a person’s life. By contrast, the most common clinical treatment for wet age-related macular degeneration involves monthly injections into the eye in a procedure that takes around 15 minutes and involves significant NHS resources.

While gene therapy studies show encouraging results, the effectiveness of retinal gene therapy may be hampered by the body’s response. Increasing evidence from clinical trials highlights problems associated with inflammation of the eye and loss of vision in patients undergoing this experimental treatment. This major problem of inflammation must be addressed if gene therapy is to be successful in the eye, and deliver what could be the most significant advancement in decades in the treatment and wellbeing of people with conditions that lead to sight loss and blindness.

What is the aim of the project?

Gene therapy in the eye commonly relies on the use of the adeno-associated virus (AAV) as the vector that carries the therapeutic gene. Inflammation is triggered by the body’s immune response, which recognises AAV as potentially harmful.

Dr Copland’s project will explore the theory that administration of AAV vectors disrupts the normal function of retinal microglia (resident immune cells in the retina), resulting in long-term changes to the health and function of the retina that contribute to chronic or persistent inflammation.

Using a disease model that replicates the inflammation reported in clinical trials of AAV, Dr Copland’s team will isolate specific subsets of retinal microglia, and immune cells that infiltrate the retina, to understand what changes are occurring at the genetic level in response to AAV. Laboratory tests will be designed to provide a comprehensive characterisation of the immune response to both high and low doses of AAV. High resolution imaging will allow researchers to monitor changes within the eye, correlating the timing of the injection, the activation of the retinal microglia, and the infiltration of immune cells.

How will this research help to beat sight loss faster?

This much needed data will highlight the cellular and molecular mechanisms that are contributing to inflammation and potentially limiting the effectiveness of gene therapy as seen in patients receiving experimental treatment.

Gene therapy has been proven to be successful in treating inherited genetic disorders, which are comparatively straightforward diseases because abnormal immune responses do not present a complicating factor. The results of Dr Copland’s study will have great potential to help advance genetic treatments for more complex, immune-mediated eye diseases, such as uveitis and age-related macular degeneration (AMD), which are thought to be regulated by an abnormal immune response.

Thank you

We are immensely grateful for the generosity of the T F C Frost Charitable Trust and of the Thriplow Charitable Trust in funding this important project.

Further information

Further information about eye conditions can be found here.