Broad spectrum antiangiogenic treatment for ocular neovascular diseases.
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.


RESULTS
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 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.


CONCLUSIONS
Lodamin, 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.
Benny
Ofra
O
Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America. ofra.bennyratsaby@childrens.harvard.edu
Nakai
Kei
K
Yoshimura
Takeru
T
Bazinet
Lauren
L
Akula
James D
JD
Nakao
Shintaro
S
Hafezi-Moghadam
Ali
A
Panigrahy
Dipak
D
Pakneshan
Pouya
P
D'Amato
Robert J
RJ
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D000818:Animals; D003510:Cyclohexanes / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D011917:Rats, Inbred Lew; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D016207:Cytokines; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol
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