Regulating the bioactivity of placental growth factor in the aging outer retina as a new therapeutic approach to age-related macular degeneration

  • Fiona Cunningham

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Age-related macular degeneration (AMD) is a sight-threatening disease caused by degeneration of the macula. Late disease presents as neovascular AMD (NV-AMD) or geographic atrophy (GA). Advances in angiogenesis research have led to the development of treatments for patients with NV-AMD. However, there are no clinically available treatments for GA. Placental growth factor (PlGF) is a seemingly dispensable member of the VEGF family, in normal physiology. However, it has been shown to propagate retinal pathology in animal models. Reports also suggest that PlGF can induce epithelial cell dysfunction and its inhibition has shown efficacy in a mouse model of GA. In this thesis, it was hypothesised that PlGF can induce dysfunction of retinal pigment epithelium (RPE), and its inhibition can attenuate pathology in a sodium iodate (NaIO3) model of GA.

In chapter 2 PlGF and its receptors were detected in human macula in late AMD and could be detected in cultured RPE. PlGF treatment of RPE increased permeability via ERK1/2 signalling and altered ZO-1 localisation. In chapter 3 the anti-PlGF antibody THR-317 inhibited the effects of PlGF on RPE, however could not protect against hypoxia or oxidative stress. In a co-culture model, THR-317 improved barrier resistance without altering the choroidal phenotype of endothelial cells. In chapter 4 PlGF inhibition provided some protection against RPE degeneration in the NaIO3 model. However, it did not protect against secondary complications and losses in visual function.

In conclusion, while PlGF and its receptors may be present in the human macula and can regulate RPE permeability, targeting PlGF is unlikely to be protective during GA. However, this should not detract from the value of PlGF as a target during outer retinal neovascular disease. The dispensable role for PlGF in maintenance of choroidal phenotype suggests it is a potentially safer target than the vasotrophic factor VEGF-A.
Date of AwardJul 2021
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsNorthern Ireland Department for the Economy & Oxurion nv
SupervisorAlan Stitt (Supervisor) & Imre Lengyel (Supervisor)

Keywords

  • Age-related macular degeneration
  • placental growth factor
  • retinal pigment epithelium
  • geographic atrophy
  • Choriocapillaris
  • Sodium iodate model

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