Early trigger of diabetic retinopathy identified
A team led by UCL scientists has identified a key protein that triggers diabetic retinopathy. The research in mice has the potential to revolutionise how the disease is treated, shifting the treatment from managing late-stage damage to preventing vision loss before it begins.
The findings published in Science Translational Medicine reveal that a protein called LRG1 plays a critical role in initiating the earliest stage of retinal damage after diabetes develops. LRG1 initiated retinal microvascular dysfunction by modifying transforming growth factor–β (TGFβ) signaling in pericytes, driving transdifferentiation to a more contractile fibrotic phenotype, resulting in narrower capillaries and thickened basement membrane. These early vascular changes impaired retinal blood flow and oxygen delivery, consistent with a defect in visual transduction.
Importantly, when researchers blocked LRG1 activity in mouse models of diabetes, they were able to prevent this early damage and preserve healthy eye function.
Way to protect vision before serious damage occurs
Lead author Dr Giulia De Rossi (UCL Institute of Ophthalmology) said: “Our discovery shows that diabetic eye disease starts earlier than we thought, and LRG1 is a key culprit in this early damage. Targeting this protein could give us a way to protect vision before serious damage occurs and prevent, rather than treat, blindness in millions of people living with diabetes.”
This new research shows that LRG1 starts causing eye damage far earlier than VEGF, making it a promising new therapeutic target. Unlike current treatments, a treatment that blocks LRG1 could intervene before vision deteriorates and prevent disease progression altogether.
Dr Faye Riley, research communications lead at Diabetes UK who part-funded the research, commented: “Nearly a third of adults with diabetes have some signs of retinopathy, and it is one of the most feared complications of the condition. By identifying the root cause of early damage, and offering a new path for treatment, this research holds immense promise for protecting the sight of the growing number of people with diabetes worldwide.”
Tried and tested LRG1-targeting drug
The UCL-based researchers have already developed a tried and tested LRG1-targeting drug, which is currently undergoing further pre-clinical studies and could be ready for clinical trials in humans in the near future. The researchers believe this therapy will not only halt the onset of diabetic retinopathy but can also be effective in later stage disease where LRG1 continues to play a role.
This work, funded by Diabetes UK, Moorfields Eye Charity and Wellcome, is the culmination of several years of research into the role of LRG1 in ocular disease undertaken by the group at the UCL Institute of Ophthalmology. Co-authors Professors John Greenwood and Stephen Moss had previously led the way in discovering LRG1 and its role in eye disease. In 2019 they launched Senya Therapeutics, a UCL spinout, formed with the support of UCL Business, to develop LRG1-targeting drugs.
Co-author Professor John Greenwood (UCL Institute of Ophthalmology), world expert in LRG1 biology, said: “This study delivers vital insight into the disease and shows that therapeutic targeting of LRG1 has real clinical potential. The discovery that LRG1 is an early initiating factor driving diabetic retinopathy is enormously exciting.”
Co-author Professor Emeritus Stephen Moss (UCL Institute of Ophthalmology) added: “The good news to accompany these findings is that we have already developed an LRG1 therapeutic ready for clinical trials. This could provide an effective new option for patients, especially those in the early stages of disease who don’t respond to existing treatments.”
Dr Ailish Murray, director of grants and research at Moorfields Eye Charity, said: “The early stages of diabetic retinopathy are often difficult to detect, leaving many people with irreversible damage once the symptoms have occurred. This research offers an important and vital next step in helping to prevent this disease, offering the chance to save the sight of millions of people living with diabetes now and in the future.”