Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease

Anbukkarasi, Muniyandi; Hartman, Gabriella D.; Yang, Song; Mijit, Mahmut; Kelley, Mark R.; Corson, Timothy W.

doi:10.1124/jpet.122.001563

Cited by 11 publications

(6 citation statements)

References 142 publications

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“…Moreover, as our understanding of the molecular mechanisms underlying various retinopathies increases and the pivotal role played by mitochondria in most oxidative stress-derived ophthalmic pathologies becomes evident, new targets come to the attention of scientists working on the development of novel and more effective therapeutic drugs [ 129 ]. These drugs could be directly developed and formulated for delivery through topical nanotechnological methods [ 130 ].…”

Section: Discussionmentioning

confidence: 99%

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies

Russo,

Rusciano,

Santangelo

et al. 2024

Medicina

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Antioxidants, usually administered orally through the systemic route, are known to counteract the harmful effects of oxidative stress on retinal cells. The formulation of these antioxidants as eye drops might offer a new option in the treatment of oxidative retinopathies. In this review, we will focus on the use of some of the most potent antioxidants in treating retinal neuropathies. Melatonin, known for its neuroprotective qualities, may mitigate oxidative damage in the retina. N-acetyl-cysteine (NAC), a precursor to glutathione, enhances the endogenous antioxidant defense system, potentially reducing retinal oxidative stress. Idebenone, a synthetic analogue of coenzyme Q10, and edaravone, a free radical scavenger, contribute to cellular protection against oxidative injury. Epigallocatechin-3-gallate (EGCG), a polyphenol found in green tea, possesses anti-inflammatory and antioxidant effects that could be beneficial in cases of retinopathy. Formulating these antioxidants as eye drops presents a localized and targeted delivery method, ensuring effective concentrations reach the retina. This approach might minimize systemic side effects and enhance therapeutic efficacy. In this paper, we also introduce a relatively new strategy: the alkylation of two antioxidants, namely, edaravone and EGCG, to improve their insertion into the lipid bilayer of liposomes or even directly into cellular membranes, facilitating their crossing of epithelial barriers and targeting the posterior segment of the eye. The synergistic action of these antioxidants may offer a multifaceted defense against oxidative damage, holding potential for the treatment and management of oxidative retinopathies. Further research and clinical trials will be necessary to validate the safety and efficacy of these formulations, but the prospect of antioxidant-based eye drops represents a promising avenue for future ocular therapies.

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Section: Discussionmentioning

confidence: 99%

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies

Russo,

Rusciano,

Santangelo

et al. 2024

Medicina

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“…The role of canonical VEGF/VEGFR signaling in the context of HHcy-induced endothelial migration and proliferation impairment are contradictory [26][27][28]. Though the suppression of canonical VEGF signaling has been mostly implicated in angiogenic defects and endothelial dysfunction, several independent angiogenic factors [68] as well as alternative mechanisms beyond VEGF signaling are gaining immense importance recently in this regard [32,69,70]. In our sub-lethal Hcy treated endothelial cells we found that the transcript levels of canonical VEGF/VEGFR signaling markers are not reduced.…”

Section: Discussionmentioning

confidence: 99%

Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through Adaptive UPR Activation and Metabolic Rewiring

Chatterjee,

Fatima,

Seth

et al. 2024

Cells

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Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. The previous literature suggests that HHcy is a strong risk factor for cardiovascular diseases. Severe HHcy is well-established to correlate with vascular pathologies primarily via endothelial cell death. Though moderate HHcy is more prevalent and associated with an increased risk of cardiovascular abnormalities in later part of life, its precise role in endothelial physiology is largely unknown. In this study, we report that moderate elevation of Hcy causes endothelial dysfunction through impairment of their migration and proliferation. We established that unlike severe elevation of Hcy, moderate HHcy is not associated with suppression of endothelial VEGF/VEGFR transcripts and ROS induction. We further showed that moderate HHcy induces a sub-lethal ER stress that causes defective endothelial migration through abnormal actin cytoskeletal remodeling. We also found that sub-lethal increase in Hcy causes endothelial proliferation defect by suppressing mitochondrial respiration and concomitantly increases glycolysis to compensate the consequential ATP loss and maintain overall energy homeostasis. Finally, analyzing a previously published microarray dataset, we confirmed that these hallmarks of moderate HHcy are conserved in adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic rewiring as two key mechanistic signatures in moderate HHcy-associated endothelial dysfunction. As HHcy is clinically associated with enhanced vascular inflammation and hypercoagulability, identifying these mechanistic pathways may serve as future targets to regulate endothelial function and health.

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“…As NV driven by VEGF-A is responsible for the blindness that occurs with AMD and DR [ 3 , 5 ], clinical trials of the most widely-used anti-VEGF therapeutics, as well as comparative studies among them, have regarded visual gains as an accepted metric of therapeutic efficacy [ 5 , 35 ]. However, being multifactorial disorders [ 43 ], increasing attention is being paid to the overarching influence of pathological processes like inflammation [ 5 , 9 ], including the effects the interplay between pathophysiological conditions, VEGFR1 ligands, pro-inflammatory factors, and the cells from which they originate, have upon the pathogenesis and progression of AMD and DR [ 7 , 9 , 44 , 45 ]. In fact, the effects of inflammation are such that research is currently being pursued on a number of anti-inflammatory therapeutics with novel targets acting via non-VEGF pathways [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1

Moon,

Kim,

Kim

et al. 2024

PLoS ONE

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In previous animal model studies, we demonstrated the potential of rAAV2-sVEGFRv-1, which encodes a truncated variant of the alternatively spliced soluble version of VEGF receptor-1 (VEGFR1), as a human gene therapy for age-related macular degeneration (AMD) and diabetic retinopathy (DR). Here, we elucidate in vitro some of the mechanisms by which rAAV2-sVEGFRv-1 exerts its therapeutic effects. Human umbilical vein endothelial cells (HUVECs) were infected with rAAV2-sVEGFRv-1 or a control virus vector in the presence of members of the VEGF family to identify potential binding partners via ELISA, which showed that VEGF-A, VEGF-B, and placental growth factor (PlGF) are all ligands of its transgene product. In order to determine the effects of rAAV2-sVEGFRv-1 on cell proliferation and permeability, processes that are important to the progression AMD and DR, HUVECs were infected with the therapeutic virus vector under the stimulation of VEGF-A, the major driver of the neovascularization that characterizes the forms of these conditions most associated with vision loss. rAAV2-sVEGFRv-1 treatment, as a result, markedly reduced the extent to which these processes occurred, with the latter determined by measuring zonula occludens 1 expression. Finally, the human microglial HMC3 cell line was used to show the effects of the therapeutic virus vector upon inflammatory processes, another major contributor to angiogenic eye disease pathophysiology, with rAAV2-sVEGFRv-1 reducing therein the secretion of pro-inflammatory cytokines interleukin (IL)-1β and IL-6. Combined with our previously published in vivo data, the in vitro activity of the expressed transgene here further demonstrates the great promise of rAAV2-sVEGFRv-1 as a potential human gene therapeutic for addressing angiogenic ocular conditions.

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Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease

Cited by 11 publications

References 142 publications

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies

Options for Topical Treatment of Oxidative Eye Diseases with a Special Focus on Retinopathies

Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through Adaptive UPR Activation and Metabolic Rewiring

An examination of the mechanisms driving the therapeutic effects of an AAV expressing a soluble variant of VEGF receptor-1

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