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Endothelial cells derived from patients with diabetic macular edema recapitulate clinical evaluations of anti-VEGF responsiveness through the Neuronal Pentraxin 2 pathway

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posted on 13.08.2020 by Ada Admin, Marta Vila Gonzalez, Magdalini Eleftheriadou, Sophia Kelaini, Hojjat Naderi-Meshkin, Shonagh Flanagan, Stephen Stewart, Gianni Virgili, David J. Grieve, Alan W. Stitt, Noemi Lois, Andriana Margariti
Diabetic macular edema (DME) remains a leading cause of vision loss worldwide. DME is commonly treated with intravitreal injections of vascular endothelial growth factor (VEGF) neutralising antibodies. Anti-VEGFs are effective but not all patients fully respond to them. Given their potential side effects, inconvenience and high cost, identifying who may not respond appropriately to anti-VEGFs and why is essential.

Herein, we determine first the response to anti-VEGFs in a cohort of DME patients using spectral-domain optical coherence tomography scans obtained throughout the first year of treatment. We found that in 28% of eyes full clearance of fluid occurred at any time during the first year (“full responders”); in 66% fluid cleared only partly (“partial responders”); in 6% fluid remained unchanged (“non-responders”). To understand this differential response, we generated induced pluripotent stem cells (iPS) from “full responders” and “non-responders” and from diabetic subjects with no DME and age-matched non-diabetic volunteers and differentiated them into endothelial cells (iPS-ECs). Monolayers of iPS-ECs derived from diabetics showed marked and prolonged increased permeability upon exposure to VEGF when compared with non-diabetic controls; the response was significantly exaggerated in iPS-ECs from “non-responders” when compared with “full responders”. Moreover, phosphorylation of key cellular proteins in response to VEGF, including VEGFR2, and gene expression profiles, such as Neuronal Pentraxin 2 (NPTX2) expression, differed between “full responders” and “non-responders”.

In the current study, iPS were used to predict patient response to anti-VEGF and identify key mechanisms underpinning the differential outcomes observed in the clinic. This approach has identified NPTX2 as playing a significant role in patient-linked responses and has potential as a new therapeutic target for DME.

Funding

This work was supported by grants from the MRC, BBSRC, and British Heart Foundation

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