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(Investigative Ophthalmology and Visual Science. 2004;45:635-640.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0735
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Inhibition of Choroidal Neovascularization in Rats by the Urokinase-Derived Peptide Å6

Hyoung J. Koh,1,2 Kenichiro Bessho,1 Lingyun Cheng,1 Dirk-Uwe Bartsch,1 Terence R. Jones,3 Germain Bergeron-Lynn,1 and William R. Freeman1

1From the Joan and Irwin Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, California; the 2Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea; and 3Ångstrom Pharmaceuticals, San Diego, California.

PURPOSE To evaluate the inhibitory effects of a urokinase-derived octapeptide Å6 on laser-induced choroidal neovascularization (CNV).

METHODS. In the first arm of the study, subcutaneous injection of Å6 (200 mg/kg per day) into the right eyes in 20 rats and phosphate-buffered saline in 20 control rats was started 1 day before laser injury. Angiography was performed at week 2. To evaluate the dose response, a second arm of the study was performed in the left eyes. Half of the treatment group was treated with 400 mg/kg per day, and the remaining half continued to receive 200 mg/kg per day beginning on week 4. Laser injury was made at week 5 and angiography was performed at week 7. Angiographic evaluation, histopathologic evaluation including maximum CNV thickness and factor-VIII–stained endothelium counting were performed in the second arm of the study. Choroidal concentrations of Å6 were measured.

RESULTS. In the first arm of the study, angiography showed a 40.8% reduction in CNV in the 200-mg/kg per day treatment group, compared with the control (P = 0.0008). In the second arm of the study, angiographic reduction in CNV was 37.9% in the 200-mg/kg per day group (P = 0.0314) and 70.0% in the 400-mg/kg per day group (P = 0.0124), compared with the control. CNV was significantly less in the 400-mg/kg per day group than in the 200-mg/kg per day group (P = 0.0393). Both CNV thickness and number of endothelial cells were reduced in a dose-dependent manner and significantly less than in the control (P < 0.05). Mean choroidal concentration of Å6 2 hours after injection was 0.72 µM in the 200-mg/kg per day (100 mg/kg every 12 hours) and 1.75 µM in the 400-mg/kg per day (200 mg/kg every 12 hours) treatment groups. Levels at 11 hours after injections were undetectable.

CONCLUSIONS. Å6 demonstrated antiangiogenic properties in a rat model of CNV and may be useful in the treatment of CNV.






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