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Breda Walsh, Sara Weis, Samir Patel, David Cheresh; Combined targeting of VEGF and PDGF to reverse neovascularization and prevent fibrosis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2298.
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Despite a solid rationale for developing anti-VEGF therapy for age-related macular degeneration (AMD), the clinical benefit appears to be short-lived and is associated with retinal fibrosis. We previously reported that while VEGF inhibition suppresses endothelial cell proliferation, it creates a stimulatory effect on the perivascular cells by enhancing PDGFRβ activity. We therefore examined the potential for combined inhibition of VEGF and PDGF to disrupt pathological angiogenesis and fibrosis.
We utilized two models to evaluate the anti-angiogenic/fibrotic effects of the anti-PDGF aptamer Fovista and the “VEGF trap” Eylea as monotherapy vs. combination therapy. To evaluate their impact on retinal angiogenesis, neonatal BalbC mouse pups were given a single intravitreal injection of Fovista (3.75µg) ± Eylea (1.25 µg) on post-natal day 5 and retinas were harvested after 6 days. To assess cellular elements and impact on fibrosis, nu/nu mice bearing subcutaneous colon carcinoma xenografts received intraperitoneal injections of 6.25 mg/kg Fovista or 2.5 mg/kg Eylea twice weekly, then tumors were harvested after 10 days. Tissues were stained for CD31, desmin, αSMA, and Masson’s trichrome as markers of angiogenesis and fibrosis and examined using confocal and light microscopy.
Anti-PDGF or -VEGF monotherapy produced a minimal anti-angiogenic effect on the development of the deep plexus layer in the retina, while their combination produced a partial block in 20% and a complete block in 80% of the retinas compared to each contralateral eye treated with vehicle control. Similarly, only the combination of Fovista plus Eylea significantly reduced tumor volume (-47±5%, P=0.008) and had the most profound effect on vascular proliferation, perivascular cell proliferation, and fibrosis within the tumor microenvironment.
Our results highlight new mechanisms underlying the benefit of dual PDGF/VEGF inhibition in diseases with pathological angiogenesis. Relative to monotherapy, combining Fovista and Eylea not only provided a more robust suppression of angiogenic sprouting, but also reduced perivascular cell accumulation and fibrosis. These results support the continued development of VEGF/PDGF inhibitor combination therapy for diseases such as AMD and cancer that are complicated by aberrant angiogenesis and fibrosis.
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