Retinopathy of prematurity: inflammation, choroidal degeneration, and novel promising therapeutic strategies

Abstract

Retinopathy of prematurity (ROP) is an important cause of childhood blindness globally, and the incidence is rising. The disease is characterized by initial arrested retinal vascularization followed by neovascularization and ensuing retinal detachment causing permanent visual loss. Although neovascularization can be effectively treated via retinal laser ablation, it is unknown which children are at risk of entering this vision-threatening phase of the disease. Laser ablation may itself induce visual field deficits, and there is therefore a need to identify targets for novel and less destructive treatments of ROP. Inflammation is considered a key contributor to the pathogenesis of ROP. A large proportion of preterm infants with ROP will have residual visual loss linked to loss of photoreceptor (PR) and the integrity of the retinal pigment epithelium (RPE) in the macular region. Recent studies using animal models of ROP suggest that choroidal degeneration may be associated with a loss of integrity of the outer retina, a phenomenon so far largely undescribed in ROP pathogenesis. In this review, we highlight inflammatory and neuron-derived factors related to ROP progression, as well, potential targets for new treatment strategies. We also introduce choroidal degeneration as a significant cause of residual visual loss following ROP. We propose that ROP should no longer be considered an inner retinal vasculopathy only, but also a disease of choroidal degeneration affecting both retinal pigment epithelium and photoreceptor integrity.

Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a Potential Antiangiogenic Gene Therapy

“…Although anti-VEGF therapeutic strategies have been employed thus far, the involvement of additional cellular factors 30 and symptoms beyond angiogenesis 2,27,29 show that neovascular retinal diseases are multifactorial conditions for which currently available treatments may be inadequate to address. Additionally, these treatments require frequent administration on a long-term basis, 3 from which other issues may arise, including safety concerns.…”

Extracellular vesicles and their miRNA cargo in retinal health and degeneration: mediators of homeostasis, and vehicles for targeted gene therapy

“…For example, our network analysis indicates that the top 10 miRNA are controlling genes associated with Interleukin and chemokine signaling, with both of these biological pathways involved in a plethora of retinal degenerative diseases (Rutar, Natoli et al 2015, Wooff, Man et al 2019 From these collective findings, we propose that in normal retinal health, exosomes are secreted from photoreceptor cells, and are released to the surrounding retina to maintain a homeostatic environment. However, following photoreceptor cell death, we hypothesize that immune responses are no longer able to be regulated due to reduced exosome numbers and the bioavailability of miRNA cargo; leading to the upregulation of inflammatory pathways, infiltration and activation of microglia/macrophages and progressive retinal cell death ( Figure 8); characteristic features of retinal degenerative diseases (Kauppinen, Paterno et al 2016, Rivera, Holm et al 2017, Rübsam, Parikh et al 2018, Wooff, Man et al 2019). Under normal homeostatic conditions, exosomes laden with miRNA, including miR-124, let-7, miR-125 and miR-183, potentially originating from photoreceptors, are continuously trafficked between retinal neurons and glial cells.…”

Vascular Regeneration for Ischemic Retinopathies: Hope from Cell Therapies

“…17 Other factors involved in ROP pathogenesis are reactive oxygen species (ROS), and inflammatory responses, which mostly involve interleukin-1β and tumor necrosis factor-α. 18,19 Figure 1. Retinal diseases associated to ischemia.…”

“…Despite their effectiveness in destroying the avascular retina and preventing neovascularization, these treatments can also lead to additional visual impairment. 18 The use of anti-VEGF drugs, such as Bevacizumab, is considered more efficient in eliminating neovascularization in the ROP retina. 21 However, there are some disadvantages with anti-VEGFs, since this approach does not completely ablate pathological neovascularization, and it also slows down physiological angiogenesis.…”

“…Moreover, it may negatively impact on the functionality of other cells within the retina, such as neurons and photoreceptors. 14,18 Vessel loss in phase one of ROP is critical in the development of the disease. Hence, the need for novel interventions at an early stage to repair the retinal vasculature.…”