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Lab for Retinal Cell Biology

Protection of retinal blood vessels in diabetic retinopathy (DR)

Ioanna Tsioti, Antonia Weh

Diabetic Retinopathy (DR) is a disease of retinal vasculature that is caused by abnormal blood glucose levels [1]. This results in retinal hypoxia and neovascularization [2]. Neovascularization is driven by vascular endothelial growth factor-a (VEGFA) [3, 4], thus intraocular injections of anti-VEGFA drugs have been used in DR patients [5, 6]. However, anti-VEGFA treatments have to be administrated repeatedly to sustain their efficacy, leading to high risk of ocular inflammation as well as to financial burden enhancement for the patients [7]. Our project aims to further develop and test an innovative dual active phosphodiesterase 5 (PDE5) inhibitor, TOP-V122 to improve vascular complications through nitric oxide (NO) release and cyclic guanosine monophosphate (cGMP) cellular levels enhancement.

To achieve our aim, we are using induced human retinal pigment epithelial cells (iPSCs) and human retinal microvascular endothelial cells (HRMECs) as in vitro models. Subsequent to that, we perform ex vivo studies using porcine retinal explants. In order to simulate a DR phenotype, the cells and the explants will be exposed in mild hypoxia and hyperglycemia in the presence and absence of TOP-V122. Immunofluorescence (IF) and gene expression analysis for tight junctions and selective hypoxic/angiogenic markers are employed. Furthermore, cGMP levels are quantified to evaluate drug’s efficacy. Additionally, we test a TOP-V122 slow release (SR) formulation in vivo using the Ins2Akita mouse DR model. These animals develop an insulin dependent diabetes because of a point mutation in the insulin 2 gene. Heterozygous Ins2Akita mice are receiving intraocular injections of TOP-V122 formulation every 4 weeks. After 20 weeks of treatment the efficacy of the drug on disease progression is analyzed by optical coherence tomography (OCT), fluorescein angiography (FA), electroretinography (ERG) and various molecular methods. This project intents to shed light on the possibility to use TOP-V122 as innovative clinical approach to improve the life quality of people who are affected by DR. 

References
1) Frank, R.N., Diabetic retinopathy and systemic factors. Middle East Afr J Ophthalmol, 2015.22(2): p. 151-6.
2) Arden, G.B. and S. Sivaprasad, Hypoxia and oxidative stress in the causation of diabetic retinopathy. Curr Diabetes Rev, 2011. 7(5): p. 291-304.
3) Bloomgarden, Z.T., Screening for and managing diabetic retinopathy: current approaches. Am J Health Syst Pharm, 2007. 64(17 Suppl 12): p. S8-14.
4) Morello, C.M., Etiology and natural history of diabetic retinopathy: an overview. Am J Health Syst Pharm, 2007. 64(17 Suppl 12): p. S3-7.
5) Ferrara, N., VEGF and Intraocular Neovascularization: From Discovery to Therapy. Transl Vis Sci Technol, 2016. 5(2): p. 10.
6) Stewart, M.W., Anti-vascular endothelial growth factor drug treatment of diabetic macular edema: the evolution continues. Curr Diabetes Rev, 2012. 8(4): p. 237-46.
7) Bressler, N.M., et al., Early Response to Anti–Vascular Endothelial Growth Factor and Two-Year Outcomes Among Eyes With Diabetic Macular Edema in Protocol T. American Journal of Ophthalmology, 2018. 195: p. 93-100.