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Age and gender impacts effectiveness of new gene therapy treatments for eye diseases, new study finds

10 February 2025

Older women could be vulnerable to harmful inflammation from new gene therapies to treat incurable eye diseases, new research has found. The University of Bristol-led study, published in Molecular Therapy, reveal how age and gender affects inflammation caused by gene therapy treatments and could cause damage to the eye. The findings could help improve the therapy’s effectiveness for eye conditions and highlights the need for personalised treatment to reduce risk and ensure a better outcome for all patients.

Around two million people live with sight loss in the UK (1).   With more than one million blind and partially sighted people living with sight loss caused by a long-term eye health condition that cannot be reversed, such as age related macular degeneration, glaucoma, and diabetic eye disease.

Until recently, some eye diseases had been considered incurable but new gene therapy techniques have shown great promise. However, increasing evidence from clinical trials have reported problems with unexpected eye inflammation, leading to vision loss in some patients. 

Inflammation is a major challenge for this type of treatment because it can limit its effectiveness. Researchers at Bristol wanted to better understand how the eye reacts to the methods used to deliver the therapy, not the disease itself, to improve safety and effectiveness of future treatments. 

In gene therapy techniques, a harmless virus called the Adeno-Associated Virus (AAV) is modified to deliver the therapeutic genes into cells at the back of the eye helping them to function normally again and preventing disease. This delivery system is widely used in gene therapy because it can efficiently enter cells and deliver the genetic instructions needed to treat disorders, such as those which can lead to sight loss and blindness.

Scientists believe some of the adverse side effects from AAV gene therapy are caused by the immune system recognising the delivery virus as potentially harmful. This impacts the effectiveness of gene therapy either directly through inflammation or indirectly as it limits necessary dose increases.

To improve the safety and effectiveness of these gene therapies the researchers wanted to better understand these responses so they can develop management strategies.

To test this theory, the research team compared, in animal models, how both male and female eye cells of different ages (young, middle-aged, and older) responded to AAV gene therapy.

The study showed that older female’s immune cells respond differently to the delivery system, and have an increased risk of harmful reactions, causing damage to the eye. 

The research team discovered that eye cells from young male and female animal models had a similar short-term immune response. However, the way immune cells (microglia and T cells) reacted at a molecular and cellular level was different between male and female cells.

As the cells aged, researchers found the inflammation lasted longer and was more severe in both genders. While cells from older males had a consistent immune response pattern, the cells from older females had a much stronger stress and inflammation response that was linked to signs of retinal damage.

The findings suggest that both gender and age play a significant role in how the body reacts to AAV gene therapy, indicating that older women could have an increased risk of harmful reactions that might cause damage to the eye and lead to vision loss in some patients. 

Dr Alison Clare, Senior Research Associate from Bristol Medical School: Translational Health Sciences (Ophthalmology) and the study’s lead author, said: “Gene therapies are an emerging tool to treat incurable eye diseases and a leading approach being developed for treating a variety of eye disorders that lead to sight loss, including hereditary - with an approved gene therapy now available - and age-related diseases. 

“Our findings are the first to demonstrate age and sex influences the risk of significant adverse inflammatory reactions in the eye to gene therapies. The research has highlighted the critical need to separate patients for gene therapy treatment based on gender, age and risk.  It also underlines the need to understand the risk-reward benefit for gene therapy and indicates older female patients could be at risk from serious adverse effects by any prospective eye gene therapy.”

The research was supported by National Institute for Health and Care Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, Wellcome (Institutional Translation Partnership Award Fellowship), Medical Research Council (Impact Acceleration Account), Sight Research UK and The Underwood Trust.

Paper

Characterisation of the ocular inflammatory response to AAV reveals divergence by sex and age’ by Alison J. Clare, Philip M. Langer, Amy Ward, Ying Kai Chan, Andrew D. Dick, David A. Copland in Molecular Therapy [open access]

Further information

(1) RNIB: Key statistics about sight loss

About the National Institute for Health and Care Research
The mission of the National Institute for Health and Care Research (NIHR) is to improve the health and wealth of the nation through research. We do this by:

  • Funding high quality, timely research that benefits the NHS, public health and social care;
  • Investing in world-class expertise, facilities and a skilled delivery workforce to translate discoveries into improved treatments and services;
  • Partnering with patients, service users, carers and communities, improving the relevance, quality and impact of our research;
  • Attracting, training and supporting the best researchers to tackle complex health and social care challenges;
  • Collaborating with other public funders, charities and industry to help shape a cohesive and globally competitive research system;
  • Funding applied global health research and training to meet the needs of the poorest people in low and middle income countries.

NIHR is funded by the Department of Health and Social Care. Its work in low and middle income countries is principally funded through UK international development funding from the UK government.

About Wellcome  
Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, infectious disease and climate and health. 

About the Medical Research Council (MRC)
The Medical Research Council (MRC) is at the forefront of scientific discovery to improve human health. Founded in 1913 to tackle tuberculosis, the MRC now invests taxpayers’ money in some of the best medical research in the world across every area of health. Thirty-three MRC-funded researchers have won Nobel prizes in a wide range of disciplines, and MRC scientists have been behind such diverse discoveries as vitamins, the structure of DNA and the link between smoking and cancer, as well as achievements such as pioneering the use of randomised controlled trials, the invention of MRI scanning, and the development of a group of antibodies used in the making of some of the most successful drugs ever developed. Today, MRC-funded scientists tackle some of the greatest health problems facing humanity in the 21st century, from the rising tide of chronic diseases associated with ageing to the threats posed by rapidly mutating micro-organisms.

About Sight Research UK
Sight Research UK is a charity that funds pioneering research into the causes of eye disease, to develop preventative methods and more effective treatments for children and adults. For the last 35 years, we have been working to bring forward the day when sight loss is a thing of the past.

About The Underwood Trust
The Underwood Trust was created on 1 July 1973. The name derives from Underwood Lane, Paisley, Scotland, which was the childhood home of one of the founders. To charity aims to fund a wide range of activities that will positively impact individuals and the environment.

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