Abstract
Pathological neovascularization is a hallmark of late stage neovascular (wet) age-related macular degeneration (AMD) and the leading cause of blindness in people over the age of 50 in the western world. The treatments focus on suppression of choroidal neovascularization (CNV), while current approved therapies are limited to inhibiting vascular endothelial growth factor (VEGF) exclusively. However, this treatment does not address the underlying cause of AMD, and the loss of VEGF's neuroprotective can be a potential side effect. Therapy which targets the key processes in AMD, the pathological neovascularization, vessel leakage and inflammation could bring a major shift in the approach to disease treatment and prevention. In this study we have demonstrated the efficacy of such broad spectrum antiangiogenic therapy on mouse model of AMD.Methods and FindingsLodamin, a polymeric formulation of TNP-470, is a potent broad-spectrum antiangiogenic drug. Lodamin significantly reduced key processes involved in AMD progression as demonstrated in mice and rats. Its suppressive effects on angiogenesis, vascular leakage and inflammation were studied in a wide array of assays including; a Matrigel, delayed-type hypersensitivity (DTH), Miles assay, laser-induced CNV and corneal micropocket assay. Lodamin significantly suppressed the secretion of various pro-inflammatory cytokines in the CNV lesion including monocyte chemotactic protein-1 (MCP-1/Ccl2). Importantly, Lodamin was found to regress established CNV lesions, unlike soluble fms-like tyrosine kinase-1 (sFlk-1). The drug was found to be safe in mice and have little toxicity as demonstrated by electroretinography (ERG) assessing retinal and by histology.ConclusionsLodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad-spectrum antiangiogenic drug that can be administered orally or locally to treat corneal and retinal neovascularization. Several unique properties make Lodamin especially beneficial for ophthalmic use. Our results support the concept that broad spectrum antiangiogenic drugs are promising agents for AMD treatment and prevention.
Highlights
Ocular neovascular-related diseases are associated with vision impairment or vision loss in millions worldwide
Our results support the concept that broad spectrum antiangiogenic drugs are promising agents for age-related macular degeneration (AMD) treatment and prevention
Using the choroidal neovascularization (CNV) model in mice and rats, our findings demonstrated the potency of Lodamin as a broad-spectrum antiangiogenic ophthalmic drug in inhibiting neovascularization, edema and inflammation by targeting numerous molecular pathways in addition to vascular endothelial growth factor (VEGF)
Summary
Ocular neovascular-related diseases are associated with vision impairment or vision loss in millions worldwide. Antiangiogenic strategies could be beneficial in preventing and treating the progression of these diseases. Corneal neovascularization is often the result of inflammation, chemical burns, and conditions related to hypoxia[1,2]. These conditions are currently treated by indirect angiogenesis inhibitors such as steroids and immunosuppressants[1]. Inhibition of retinal nonvascular disease, such as AMD, has been focused on targeting the angiogenic factor VEGF and these therapies are the current gold standard in the treatment of neovascular AMD
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