Investigation of adverse side-effects of anti-VEGF therapy in the diabetic retina
Dr Heping Xu will study the safety of anti-VEGF therapy, which is used to treat the leakage of fluid from damaged blood vessels at the back of the eye (diabetic macular oedema). He will find out which cells in the retina are most at risk from such therapy over time and if the damage caused can be reversed when therapy is stopped.
Background to research
Diabetic macular oedema (DMO) is a major cause of vision loss during diabetic retinopathy. DMO is caused by leakage of fluid from damaged blood vessels into the central part of the retina at the back of the eye (a region known as the macula). A protein called vascular endothelial growth factor (VEGF) increases the permeability of the blood vessels and therefore plays a key role in DMO development. Biological treatments that block VEGF have now become an established treatment for DMO. Ranibizumab (Lucentis) is the VEGF inhibitor that is licensed to treat DMO in the UK and, for many people, leads to better vision outcomes than conventional laser therapy. Despite the problems it can cause, VEGF in the retina is essential for cell survival and function. Anti-VEGF therapy for 7-8 years led to accelerated breakdown of tissue in the retina in around 54% of people with age-related macular degeneration. Furthermore, in a pilot study, Dr Heping Xu and colleagues at the University of Belfast found that the retina deteriorated over time when VEGF was genetically removed from the eyes of diabetic mice, but was less of a problem in non-diabetic mice. The exact reasons for this are unknown, but Dr Xu is concerned that long-term anti-VEGF therapy in people with DMO might cause severe damage to their eyes.
With funding from Diabetes UK, Dr Heping Xu will study the safety of anti-VEGF therapy in diabetic eyes. He will find out which cells in the retina are most at risk from loss of VEGF over time and if the damage caused by anti-VEGF therapy can be reversed when therapy is stopped. The researchers will inject a VEGF inhibitor into the eyes of mice with and without diabetes using a technique similar to that used in people with DMO. The function of nerves and blood vessels at the back of the eye will then be tested at different times. Therapy will be stopped when retinal damage becomes obvious and the animals will be monitored for a further few months to see if damage is reversed. To understand which cells in the retina are damaged by blocking VEGF, the researchers will also study the effects of VEGF inhibitors on different types of retinal cells grown in the lab under normal and high glucose conditions.
Potential benefit to people with diabetes
This research will provide evidence on the likelihood of long-term damage to the retina and the potential impact on visual function of anti-VEGF therapy. This will help to improve long-term management of DMO and could have an immediate impact on people with diabetes by helping clinicians to limit the side effects of this new and widely used treatment. Specifically, the results will help clinicians to decide which patients are most likely to benefit from anti-VEGF therapy, and allow them to put in place schemes to monitor the function of the retina after therapy. It’s possible that the researchers will also uncover novel mechanisms related to the long-term side effects of anti-VEGF therapy, although this aspect of the research may take longer to translate into improved therapy.