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Proliferative Diabetic Retinopathy: Pathophysiology and Management Strategy

Dr. Mohd Imtiaz Nawaz, King Saud University (KSU), Riyadh, KSA

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Abstract:
Proliferative diabetic retinopathy (PDR) is the most common diabetes-related eye disease and is a leading cause of visual impairment worldwide.

In my ten years of research work, we reported for the first time the involvement of novel chemokines and cytokines in the progression of PDR. We found that high-mobility group box-1, platelet factor-4, heparanase-1, acyl-glycerol kinase, endocan, matrix metallopeptidases, CXCL16, and few other angio-inflammatory markers, including neurotrophins, are the biomarkers of the disease.

The proangiogenic vascular endothelial growth factor (VEGF) exerts a pathogenic role in PDR and is responsible for blood-retina barrier breakdown, increased vessel permeability, and retinal neovascularization. As opposed to the hundreds of scientific literatures, we demonstrated that the VEGF in PDR vitreous fluid is present at concentrations 1000-100000-fold higher than those traditionally reported. This finding anticipates that the novel strategies aimed at unmasking vitreal- VEGF may increase the potency of VEGF blockers, with therapeutic implications for PDR patients.

Our research work is a pioneer in demonstrating the use of vitreous fluid obtained from PDR patients as a translational research tool. We developed a novel 3D-endothelial cell spheroid/human vitreous assay, a first of its type, for a rapid and cost-effective experimental procedure suitable for evaluating the anti-angiogenic activity of novel extracellular and intracellular drug candidates using PDR vitreous fluid as a proangiogenic stimulus. Indeed, our study may provide evidence to recapitulate the events occurring during PDR progression. This could set the basis for designing preclinical experiments to test pharmaceutical drugs for the early treatment of PDR.

Our data suggest that the human PDR vitreous is biologically active and induces a proangiogenic/proinflammatory phenotype in endothelial cells. The data indicate that inflammation mediates the angiogenic activity of PDR vitreous fluid and that N-formyl peptide receptors (FPRs) may mediate these responses. Thus, FPR may represent a target for developing novel anti- inflammatory/anti-angiogenic approaches for PDR therapy.

Next, I worked on a project aimed to investigate the angiogenic activity of enantiomers of novel short peptides, with potential implications in the management of PDR or ischemic disease. The peptide N-tert-butyloxycarbonyl (Boc)-Phe-D-Leu-Phe-D-Leu-Phe (BOC2) has been used extensively as an FPR1/FPR2 antagonist to assess the role of FPRs in physiological and pathological conditions. However, our data have shown that the BOC2-related peptide Boc-Phe-Leu-Phe-Leu-Phe (BOC- FLFLF in single letter code, L-BOC2) having all-L configurations on its stereocenters, inhibits the angiogenic activity of various heparin-binding angiogenic growth factors, including VEGF-A165, by interacting with their heparin-binding domain. Thus, BOC2 can be used as a multi-target candidate with a potential therapeutic implication in angiogenesis-dependent diseases, including cancer.

Surprisingly, we found that at variance with its L-enantiomer, D-BOC2 is devoid of any VEGF antagonist activity. On the contrary, D-BOC2, as well as D-F3 and D-Succ-F3, are endowed with a significant proangiogenic capacity. Besides, we demonstrate that the angiogenic activity of D-Succ- F3 is due to the engagement and activation of FPR3 expressed by endothelial cells. In conclusion, D- Succ-F3 may set the basis for the design of novel proangiogenic peptides with potential translational implications in therapeutic angiogenesis for treating chronic wounds.

Meeting ID: 964 3744 5259
Passcode: 026375
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