Ved, NK; (2016) Anti-angiogenic therapy in treating outer barrier dysfunction in diabetic retinopathy. Doctoral thesis , UCL (University College London).

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Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness in the developed world. Characteristic features of DR are retinal neurodegeneration, pathological angiogenesis and breakdown of both the inner and outer retinal barriers of the retinal vasculature and RPE-choroid respectively. Vascular endothelial growth factor-A (VEGF), a key regulator of angiogenesis and permeability, is the target of most pharmacological interventions of DR. VEGF can be alternatively spliced at exon 8 to form 2 families of isoforms, pro- and anti-angiogenic. VEGF165 is the most abundant pro-angiogenic isoform, is pro-inflammatory and a potent inducer of permeability. VEGF165b is anti-angiogenic, anti-inflammatory, cytoprotective and neuroprotective. In the diabetic eye, pro-angiogenic VEGF isoforms are up-regulated such that they overpower VEGF165b. I hypothesised this imbalance contributed to increased breakdown of the retinal barriers and by redressing this imbalance, the pathological angiogenesis, fluid extravasation and retinal neurodegeneration could be ameliorated. VEGF165b prevented VEGF165 and hyperglycaemia-induced tight junction breakdown and subsequent increase in solute flux in retinal pigmented epithelial (RPE) cells. In streptozotocin-induced diabetes, there was an increase in Evans’ blue extravasation after both 1 and 8 weeks of diabetes, which was reduced upon intravitreal and systemic delivery of rhVEGF165b. 8-weeks diabetic rats also showed an increase in retinal vessel density, which was prevented by VEGF165b. To try to ensure sustained delivery of VEGF165b in the diabetic eye an adeno-associated virus, AAV.VEGF165b was developed and delivered subretinally. Although injection of AAV.VEGF165b resulted in effective expression of VEGF165b in the eye, this caused a detrimental effect on retinal function. These results show rhVEGF165b reduce DR-associated BRB dysfunction and angiogenesis. Although the neuroprotective effects of VEGF165b in DR are unclear, evidence from other retinopathies, neuropathy and data presented in this thesis suggest that, if the delivery systems can be optimised, VEGF165b may be a suitable therapeutic in treating DR.

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