LRG1 Protein Unmasked as Root Cause of Diabetic Blindness

A Hidden Culprit, Decades in the Making

For decades, doctors have treated diabetic eye disease only after the damage was already done. Now, scientists at University College London (UCL) have identified the molecular spark that ignites retinal destruction long before a patient notices any change in their vision — and they have a drug candidate ready to extinguish it.

The culprit is LRG1 (leucine-rich alpha-2-glycoprotein 1), a protein whose role in triggering the earliest phase of diabetic retinopathy was described in a landmark study published in Science Translational Medicine in October 2025. The findings, led by Dr. Giulia De Rossi at the UCL Institute of Ophthalmology and funded by Diabetes UK and Moorfields Eye Charity, represent one of the most mechanistically complete explanations of retinopathy onset to date.

How LRG1 Quietly Steals Sight

Diabetic retinopathy develops when high blood sugar damages the network of tiny blood vessels supplying the retina. What the UCL team discovered is that LRG1 initiates this damage at the cellular level by hijacking a critical signalling pathway. The protein alters transforming growth factor-β (TGFβ) signalling in pericytes — the support cells that wrap around capillary walls — pushing them to transform into a stiffer, more contractile state.

The result: retinal capillaries constrict, blood flow slows, and oxygen delivery to light-sensitive tissue falls. Computational modelling confirmed that even these subtle early changes are sufficient to compromise retinal oxygenation and make the tissue far more vulnerable to hypoxic injury — all before a single visible lesion appears.

In diabetic mouse models, knocking out the Lrg1 gene completely prevented this early vascular dysfunction. Normal capillary diameter was maintained, oxygen delivery was preserved, and standard measures of retinal function remained intact. Blocking LRG1 activity pharmacologically produced the same protective effect.

Why This Changes the Treatment Landscape

Current standard-of-care treatments for diabetic retinopathy target a different protein, VEGF (vascular endothelial growth factor), which drives the abnormal blood vessel growth seen in advanced disease. Anti-VEGF injections have been a major advance, but they help only around half of patients and rarely reverse damage that has already occurred.

LRG1 acts far earlier in the disease cascade than VEGF, making it a fundamentally different type of target — one aimed at prevention rather than damage control. "This discovery means we may be able to intervene at the very start of the disease process," the UCL team noted, rather than waiting for the condition to reach a treatable but already destructive stage.

A Drug Candidate Already Exists

The path from discovery to clinic is unusually short here. UCL researchers previously developed Magacizumab, a humanised antibody that blocks LRG1, originally for wet age-related macular degeneration. The same molecule is now being evaluated as a treatment for diabetic retinopathy, with final pre-clinical studies underway. A UCL spinout, Senya Therapeutics, founded in 2019 by Professors John Greenwood and Stephen Moss, is spearheading commercial development.

The Scale of the Problem

The stakes are enormous. Diabetic retinopathy affects an estimated 103 million people worldwide, and that number is projected to reach 160 million by 2045 as the global diabetes epidemic accelerates. In 2020, the condition left over one million people blind. It is the leading cause of preventable blindness among working-age adults globally, with the highest burden concentrated in South and East Asia.

For a disease that strips people of their independence and livelihoods, an intervention capable of halting the process at its very origin — rather than managing its late-stage consequences — would be transformative. If clinical trials confirm what the laboratory data strongly suggests, LRG1 inhibition could become the first genuinely preventive therapy for one of the world's most common causes of blindness.