Understanding long-term gene therapy associated uveitis on a disease background to devise appropriate management strategies

Brief plain language background 

Gene therapy is showing huge promise for treating both inherited and acquired sight threatening diseases. There is already one gene therapy treatment available to treat a form of inherited retinal degeneration, a condition which causes gradual sight loss from birth. Many more in development seek to treat millions of patients affected by conditions including age-related macular degeneration and diabetic macular oedema. Gene therapy uses a modified adeno-associated virus (AAV), to deliver these therapies. 

However, increasing evidence from clinical trials report problems with inflammation in the eye that occurs because our immune system recognises the AAV as foreign and potentially harmful. Inflammation in the eye is a significant adverse reaction, which for some patients can cause unexpected sight loss. To make gene therapy safe and effective for all patients, we need to understand more about the immune response to AAV. This way we can develop appropriate strategies to prevent the inflammation. 

What problem/knowledge gap does it help address 

Steroids are the main tool for managing the adverse inflammatory response to AAV gene therapy. Despite this immunosuppressive approach, inflammation still occurs in patients. For some disease backgrounds, such as diabetes, this response can be more significant leading to sight-loss. Modelling this response in healthy mice has identified key cells involved and potential steroid alternatives to manage inflammation. However, we lack information on how the different retinal disease background or systemic co-morbidities impact the inflammatory response. For example, we know that diabetic patients have a more severe inflammatory response to gene therapy compared to patients with wet age-related macular degeneration. To make gene therapy safe for everyone, we need to identify how and why the inflammatory response to AAV gene therapy is different for an individual that already has disease. This will better inform the way we treat the adverse effect of inflammation and ensure the gene therapy works safely. 

Aim of the project 

To highlight how inflammation to the AAV is different in disease models, with eyes vulnerable to inflammation, such as diabetes. This will be used to identify the best immunosuppressive drug to prevent the inflammation caused by gene therapy. 

Potential impact on people with sight loss 

This project will generate a comprehensive assessment of how immune responses to AAV vectors in the eye are amplified by underlying disease. This will reveal the elements that are currently limiting how effective gene therapy is for patients. It will provide new strategies that can be used to change these negative effects and improve gene therapy for future application in the eye. As the drugs we plan to test are already approved for human use, refined approaches that can limit inflammation and improve the long-term outcome of gene therapy could be implemented within clinical trials in a relatively short timeframe.