None of this would have been possible without the generous support of @diabetesuk.bsky.social, #moorfieldseyecharity, @ucltro.bsky.social and @wellcometrust.bsky.social 🙏

Also very grateful to
@ucleye.bsky.social
for being such an inspiring and supportive place to do science. 🧪

Grateful to @greenwoodjohn.bsky.social and
@stephenemoss.bsky.social
for co-leading this study with such insight and enthusiasm, and to all co-authors for their invaluable contributions.

Finally — and most importantly —
a single intravitreal injection of an LRG1-blocking antibody (15C4) significantly reduced all early vascular defects and restored visual function in diabetic mice.
🎯A potential early therapeutic strategy for preventing vision loss. 👁️

Although these vascular changes appear subtle, computational modelling revealed that they markedly impair retinal oxygenation, providing a mechanistic explanation for the reduced ERG responses seen in diabetic eyes.

This LRG1-driven pericyte dysfunction leads to pathological microvascular remodelling. We see decreased capillary density and diameter. Interestingly, this is also seen in human DR patients at high risk of progressing to the advanced stage (Nicholson et al. JAMA 2019).

Once secreted, LRG1 acts on pericytes through TGFbeta signalling, driving them toward a more contractile and fibrotic phenotype.
We observed increased myosin light chain activation and thickened basement membrane in diabetic wild-type mice, but not in those lacking Lrg1.

So we moved to diabetic mice to investigate the source and the impact of excessive LRG1 production in diabetic retinas.

We found that the inflamed retinal endothelium is the main source of LRG1 and that retinal Lrg1 expression is switched on months earlier than that of Vegf.

We found that LRG1 is increased in retinas from people with diabetes and DR, corroborating several cross-sectional proteomic studies showing correlation between plasma and vitreous LRG1 with the duration of diabetes.

We identified leucine-rich α-2-glycoprotein 1 (LRG1) as an initiator of early microvascular dysfunction in the diabetic retina and show that blocking LRG1 in mouse models of diabetes protects them from developing DR. www.science.org/doi/10.1126/...