Repurposing antimalarial aminoquinolines and related compounds for treatment of retinal neovascularization

Abstract

Neovascularization is the pathological driver of blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. The loss of vision resulting from these diseases significantly impacts the productivity and quality of life of patients, and represents a substantial burden on the health care system. Current standard of care includes biologics that target vascular endothelial growth factor (VEGF), a key mediator of neovascularization. While anti-VGEF therapies have been successful, up to 30% of patients are non-responsive. Therefore, there is a need for new therapeutic targets, and small molecule inhibitors of angiogenesis to complement existing treatments. Apelin and its receptor have recently been shown to play a key role in both developmental and pathological angiogenesis in the eye. Through a cell-based high-throughput screen, we identified 4-aminoquinoline antimalarial drugs as potent selective antagonists of APJ. The prototypical 4-aminoquinoline, amodiaquine was found to be a selective, non-competitive APJ antagonist that inhibited apelin signaling in a concentration-dependent manner. Additionally, amodiaquine suppressed both apelin-and VGEF-induced endothelial tube formation. Intravitreal amodaiquine significantly reduced choroidal neovascularization (CNV) lesion volume in the laser-induced CNV mouse model, and showed no signs of ocular toxicity at the highest doses tested. This work firmly establishes APJ as a novel, chemically tractable therapeutic target for the treatment of ocular neovascularization, and that amodiaquine is a potential candidate for repurposing and further toxicological, and pharmacokinetic evaluation in the clinic.

17β-Estradiol Delivered in Eye Drops: Evidence of Impact on Protein Networks and Associated Biological Processes in the Rat Retina through Quantitative Proteomics

“…For example, preventative, disease-modifying, or adjuvant medications that would thwart or remedy damage to retinal neurons by a group of complex and slow-progressing neurodegenerative eye diseases such as glaucoma, diabetic retinopathy, or age-related macular degeneration have remained elusive [3]. However, it has been recognized that many approved drugs can be repurposed for ocular pharmacotherapy [4,5], or utilized as direct lead compounds to develop ophthalmic pharmaceuticals [6][7][8]. Another challenge is that pathology-associated neuronal damage in the retina exhibits multiple mechanisms of yet to be understood complexity, which calls for polypharmacology (which recognizes the necessity for a single drug to exert effects on multiple targets and disease pathways) as a preventative and/or therapeutic approach [9].…”

Comparative transcriptome analysis of human and murine choroidal neovascularization identifies fibroblast growth factor inducible-14 as phylogenetically conserved mediator of neovascular age-related macular degeneration

“…These genes are known mediators of disease-relevant processes such as angiogenesis, immune response and wounding. Among them, there were several proangiogenic factors including APLNR (Hara et al, 2013;Ishimaru et al, 2017;Kasai, 2011;McAnally et al, 2018), LGALS3 (Chen et al, 2017;Jia et al, 2013;Yao et al, 2019), CYBB (Al-Shabrawey et al, 2005;Chan et al, 2013), CTSS (Chen et al, 2010;Fan et al, 2012;Wang et al, 2006), UNC5B (Lejmi et al, 2008), MCAM (Stalin et al, 2016), ADAM15 (Horiuchi et al, 2003;Hou et al, 2015;Xie et al, 2008) and KCNN4 (Grgic et al, 2005). In addition to the already known factors, the present study identifies a plethora of new conserved mediators of CNV development that represent potential therapeutic targets for neovascular AMD.…”

VEGF, apelin and HO-1 in diabetic patients with retinopathy: a correlation analysis

“…The results of this study have indicated that there may be a close relationship between VEGF, apelin, HO-1 and abnormal glucose metabolism, and they may participate in the process of PDR. Previous studies have suggested that serum apelin levels are significantly increased in patients with DR, and it are related to patients with DM, which can be used as a reliable indicator for assessing the progress of DR [ 45 , 46 ]. It can be seen that the serum levels of VEGF and apelin are high in DR patients, while the expression level of HO-1 is lower.…”