Abstract 384 Developmental Pharmacology: Drug Effects on Neonatal Angiogenesis and Vascular Function Platform, Monday, 5/3

Purpose: Squalamine is an aminosterol antibiotic that inhibits angiogenesis in tumor models. Squalamine is currently in phase I trials for advanced malignancy. The goal of the study was to determine the effect of a single dose of squalamine on oxygen induced retinopathy (OIR) in the mouse.

Methods: Oxygen induced retinopathy was produced in C57BL6 mice by a five day exposure to 75% oxygen from postnatal day 7 through 12 (P7-12). Squalamine treated animals received one dose of squalamine (25 mg/kg subcutaneously) on P12 just after removal from 75% oxygen. Animals were sacrificed at P17-21. Retinopathy was assessed by quantification of neovascular nuclei on retinal sections and by a retinopathy scoring system evaluation of retinal whole mounts.

Results: Single dose squalamine improved retinal neovascularization. Animals exposed to oxygen had an average of 46.2 ± 24.1 neovascular nuclei/retinal section whereas animals who received squalamine on P12 had 16.3 ± 6.8 neovascular nuclei/retinal section (p < 0.001). Control animals had nuclei counts (4.9 ± 3.1) which were similar to squalamine treated controls (6.6 ± 4.4). Improvement was seen in total retinopathy scores: animals receiving squalamine after oxygen exposure had a median (25th,75th quartile) retinopathy score of 4(4,6.75) whereas oxygen exposed animals had a median retinopathy score of 9(7,10) (p < 0.001). Control animals had similar retinopathy scores of 0(0,1) to those receiving only squalamine [median score of 1(0,1)]. Vehicle treatment did not affect retinopathy scores. There were no differences in neonatal growth in any of the treatment groups.

Conclusions: Single dose squalamine significantly improves retinal neovascularization in a mouse model of OIR. Squalamine did not appear to adversely affect the general health or retinal vascular development of neonatal mice. We speculate that squalamine may inhibit retinal neovascularization by blocking VEGF-stimulated angiogenesis and may be a candidate for neonatal clinical trials for ocular neovascularization.

Funded by Magainin Pharmaceuticals Inc. Equity in Magainin Pharmaceuticals, Inc. (MZ)