Study indicates age and gender are factors in ocular gene therapy outcomes

Inflammation lasted longer and was more severe in all older patient models, regardless of gender. Image credit: ©evafesenuk – stock.adobe.com

Findings from a new study via the University of Bristol indicate that age and gender may play a part in patient outcomes following ocular gene therapy. Lead author Alison Clare, PhD, BSc (hons), a senior research associate from Bristol Medical School: Translational Health Sciences (Ophthalmology), and her colleagues published the findings in Molecular Therapy. Their study focused on ocular gene therapy delivered by an adeno-associated virus (AAV) system. Patients may experience adverse effects if the immune system reacts to the delivery virus with inflammation. This can lead to decreased effectiveness of the gene therapy, either due to the inflammation itself or by creating limitations around dosing due to the adverse response.¹

The University of Bristol research team used animal models to compare patient responses to AAV therapy, studying male and female eye cells across different age groups (young, middle-aged and older patients).² Eyes of older females exhibited an increased incidence of inflammation or other reactions, which caused damage to the eye. Additionally, inflammation lasted longer and was more severe in all older patient models, regardless of gender. Older males exhibited a consistent immune response pattern, more severe than their younger male counterparts, while cells from older females had a stronger stress and inflammation response. These reactions in older female models were linked to signs of retinal cell damage. While immune cells, such as microglia and T cells, did exhibit different response characteristics among young female and young male animal models, the young animal models presented a “similar short-term immune response” regardless of gender.¹

“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,” Dr Clare said in a statement.¹ “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; global charitable foundation Wellcome, provider of the Institutional Translation Partnership Award Fellowship; the Medical Research Council’s Impact Acceleration Account; Sight Research UK and The Underwood Trust.

References

1. Age and gender impacts effectiveness of new gene therapy treatments for eye diseases, new study finds. News release. University of Bristol. Published 10 February, 2025. Accessed 10 February, 2025. https://bristol.ac.uk/news/2025/february-/gene-therapy-eyes-.html

2. Clare AJ, Langer PM, Ward A, Chan YK, Dick AD, Copland DA. Characterization of the ocular inflammatory response to AAV reveals divergence by sex and age. Mol Ther. Published online January 17, 2025. doi:10.1016/j.ymthe.2025.01.028