Novel Therapeutic Target Identified For Treatment Of Proliferative Diabetic Retinopathy Identified

MedicalResearch.com Interview with:
Akrit Sodhi, M.D., Ph.D.
Assistant Professor of Ophthalmology
Retina Division
Wilmer Eye Institute
Johns Hopkins Medical Institutions

Medical Research: What is the background for this study? What are the main findings?

Dr. Sodhi: Diabetic eye disease is the most common cause of severe vision loss in the working age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In proliferative diabetic retinopathy, retinal ischemia leads to the upregulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization, in some, but not all diabetic patients, implicating additional factor(s) in proliferative diabetic retinopathy pathogenesis. In our study, we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identified angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is upregulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from proliferative diabetic retinopathy patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of proliferative diabetic retinopathy and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.


Medical Research: What should clinicians and patients take away from your report?

Dr. Sodhi: In proliferative diabetic retinopathy (PDR), the most vision-threatening sequela of diabetic eye disease, retinal ischemia leads to increased expression of angiogenic factors that promote neovascularization. While therapies targeting the potent angiogenic mediator vascular endothelial growth factor (VEGF) have been remarkably successful for the treatment of diabetic macular edema, this approach has not proven sufficient to prevent the development of retinal neovascularization, implicating additional angiogenic factor(s) in PDR pathogenesis. We demonstrate here that angiopoietin-like 4 (ANGPTL4) is a potent angiogenic mediator with markedly increased expression in the eyes of proliferative diabetic retinopathy patients.

Our studies identify a novel therapeutic target for the treatment of ocular neovascular disease and may have broad implications for the treatment of other diseases dependent on pathologic angiogenesis.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Sodhi: The next step will be to identify effective inhibitors of ANGPTL4 (or its yet-to-be-identified receptor) and to test these inhibitors using animal models of diabetic eye disease.

Citation:

Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy,Proceedings of the National Academy of Sciences, www.pnas.org/cgi/doi/10.1073/pnas.1423765112

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Akrit Sodhi, M.D., Ph.D., Assistant Professor of Ophthalmology, Retina Division, Wilmer Eye Institute, & Johns Hopkins Medical Institutions (2015). Novel Therapeutic Target Identified For Treatment Of Proliferative Diabetic Retinopathy Identified