Blockade of sphingosine-1-phosphate reduces macrophage influx and retinal and choroidal neovascularization.
Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that stimulates endothelial cell migration, proliferation, and survival in vitro, and tumor angiogenesis in vivo. In this study, we used a humanized monoclonal antibody (sonepcizumab) that selectively binds S1P to investigate its role in retinal and choroidal neovascularization (NV). Intraocular injection of sonepcizumab significantly reduced macrophage influx into ischemic retina and strongly suppressed retinal NV in mice with oxygen-induced ischemic retinopathy. In mice with laser-induced rupture sites in Bruch's membrane, intraocular injection of sonepcizumab significantly reduced the area of choroidal NV and concomitantly reduced fluorescein leakage from the remaining choroidal NV. Four weeks after intraocular injection of up to 1.8 mg of the sonepcizumab in non-human primates, electroretinograms and fluorescein angiograms were normal, and light microscopy of ocular sections showed no evidence of structural damage. These data show for the first time that S1P stimulates both choroidal and retinal NV and suggest that sonepcizumab could be considered for evaluation in patients with choroidal or retinal NV.
Xie
Bing
B
Department of Ophthalmology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shen
Jikui
J
Dong
Aling
A
Rashid
Aymen
A
Stoller
Glenn
G
Campochiaro
Peter A
PA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D020256:Choroidal Neovascularization / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D008246:Lysophospholipids / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology; D008252:Macaca fascicularis; D008264:Macrophages / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015861:Retinal Neovascularization / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology
D000911:Antibodies, Monoclonal; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine
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