Anti-angiogenic and anti-scarring dual action of an anti-Fibroblast Growth Factor-2 aptamer in animal models of retinal diseaseView Session View Presentation
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Abstract Number: 976
AuthorBlock: Robert B. Bhisitkul1, Yusaku Matsuda2, Yosuke Nonaka2, Satoshi Futakawa2, Kazumasa Akita2, Toshiaki Nishihata2, Masatoshi Fujiwara2, Yusuf Ali2, Yoshikazu Nakamura2,3
1Ophthalmology, University California-San Francisco, San Francisco, California, United States; 2RIBOMIC, Inc., Tokyo, Japan; 3Institute of Medical Science, University of Tokyo, Tokyo, Japan;
DisclosureBlock: Robert B. Bhisitkul, RIBOMIC, USA Code C (Consultant) , Roche/Genentech Code F (Financial Support) , Merck Code R (Recipient) , AntriaBio/Rezolute Code C (Consultant) , Apellis Code F (Financial Support) , Zordera, Inc. Code I (Personal Financial Interest) , Quark Pharmaceuticals Code R (Recipient) , Yusaku Matsuda, RIBOMIC, Inc. Code E (Employment) , Yosuke Nonaka, RIBOMIC, Inc. Code E (Employment) , Satoshi Futakawa, RIBOMIC, Inc. Code E (Employment) , Kazumasa Akita, RIBOMIC, Inc. Code E (Employment) , Toshiaki Nishihata, RIBOMIC, Inc. Code E (Employment) , Masatoshi Fujiwara, RIBOMIC, Inc. Code E (Employment) , Yusuf Ali, RIBOMIC, Inc. Code E (Employment) , Yoshikazu Nakamura, RIBOMIC, Inc. Code E (Employment)
While fibroblast growth factor 2 (FGF2) initiates angiogenesis and scar formation in many tissue systems, its role in retinal diseases has not been defined. In animal models of choroidal neovascularization (CNV), we evaluated the pathogenic activity of FGF2, and the effects of a novel anti-FGF2 aptamer, RBM-007, in suppressing both angiogenesis and subretinal fibrosis.Methods
In female C57BL/6J mice, Matrigel plugs mixed with 1 µg FGF2 were implanted subcutaneously in the right flank and daily intraperitoneal doses of RBM-007 were given. At day 7 explanted plugs were assessed for vessel growth by light microscopy. Laser-induced CNV was performed in both a mouse model and a rat model (male BN rats) using 532 nm and 50 µm spot size, immediately followed by intravitreal injections with: ranibizumab, RBM-007, or combination ranibizumab + RBM-007. CNV growth was quantified by FITC-dextran infusion and preparation of choroidal flat mounts for confocal microscopy. Subretinal fibrosis was assessed histologically in paraffin-embedded whole eye sections.Results
In the mouse Matrigel plug assay, FGF2 stimulated robust new vessel growth; compared to saline vehicle, daily intraperitoneal injections of 1, 3, and 10 mg/kg produced reductions in blood vessel grades of 85, 88, and 96% respectively. In the mouse laser CNV model, at 7 days the combination of ranibizumab 10 μg/eye + RBM-007 6 μg/eye showed significant reduction in CNV area (controls mean 115426 ± 7253 (SE) pixels vs. 97478 ± 6651, p < 0.05, Dunnett’s test). In the rat CNV model, at 14 days compared to saline vehicle (mean 104534 ± 3478 pixels) significant reductions in CNV area (p < 0.05) were with found with intravitreal injection of ranibizumab 10 μg/eye (94849 ± 2159), and RBM-007 at doses of 5 to 45 μg/eye (92641 ± 2569 to 93586 ± 1964). Subretinal fibrosis formation at 6 weeks was graded and compared to saline vehicle (66.5% of spots grade 2 to 4 severity); eyes injected bi-weekly with RBM-007 15 μg/eye showed statistically significant reductions (p < 0.05) in severity of fibrosis with 2 injections (40.4%) and with 3 injections (40.6%).Conclusions
Blockade of FGF2 with intravitreal injection of the aptamer RBM-007 led to suppression of both choroidal neovascularization and subretinal fibrosis in animal models. The dual action of RBM-007 suggests a novel pathway for treatment of neovascular AMD.Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details.
Macular degeneration, a leading cause of blindness, is due to the abnormal growth of blood vessels and subsequent scarring underneath the retina. Fibroblast growth factor (FGF) has been shown to play a role in blood vessel growth (angiogenesis) and scarring in many parts of the body. In animal models, we tested whether FGF2 can cause retinal angiogenesis, and whether a new compound designed to block FGF2, known as RBM-007, can reduce both angiogenesis and scarring in the retina. In mice, FGF2 exposure produced robust angiogenesis in an experimental assay. Laser injury in mice and rats induces the growth of abnormal blood vessels under the retina similar to macular degeneration; injection of RBM-007 was seen to reduce both angiogenesis and scarring in these injured retinas. These studies indicate that RBM-007 has a dual action to protect the retina, and may in the future offer a new way to treat patients with macular degeneration and other retinal diseases.