Broad spectrum antiangiogenic treatment for ocular neovascular diseases

Ofra Benny, Kei Nakai, Takeru Yoshimura, Lauren Bazinet, James D. Akula, Shintaro Nakao, Ali Hafezi-Moghadam, Dipak Panigrahy, Pouya Pakneshan, Robert J. D'Amato

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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 Findings: Lodamin, 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 fmslike 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. Conclusions: Lodamin, a polymer formulation of TNP-470, was identified as a first in its class, broad- pectrum 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.

Original languageEnglish
Article numbere12515
Pages (from-to)1-14
Number of pages14
JournalPloS one
Volume5
Issue number9
DOIs
Publication statusPublished - 2010

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Benny, O., Nakai, K., Yoshimura, T., Bazinet, L., Akula, J. D., Nakao, S., Hafezi-Moghadam, A., Panigrahy, D., Pakneshan, P., & D'Amato, R. J. (2010). Broad spectrum antiangiogenic treatment for ocular neovascular diseases. PloS one, 5(9), 1-14. [e12515]. https://doi.org/10.1371/journal.pone.0012515