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M. Nozaki, B.J. Raisler, I. Mett, N. Notkin, I. Papismadov, L. Shalom, A. Takeda, J.Z. Baffi, E. Feinstein, J. Ambati; RTP801i: A Novel Anti–Angiogenic Strategy Superior to and Cooperative With VEGF–A Blockade in Suppressing CNV . Invest. Ophthalmol. Vis. Sci. 2006;47(13):900.
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© ARVO (1962-2015); The Authors (2016-present)
RTP801 is a novel HIF–1a–responsive gene. Recently we showed that RTP801 knockout (KO) mice have reduced pathological retinal neovascularization in experimental ROP, indicating the therapeutic potential of RTP801 inhibition for age–related macular degeneration (AMD). The purpose of this study was to demonstrate that both genetic (KO mice) and therapeutic (using specific siRNA, RTP801i) inhibition of RTP801 expression would suppress choroidal neovascularization (CNV) volume and leakage in the laser injury model.
CNV was induced by laser injury in C57BL/6J, RTP801–/– and +/+ mice, and volumes measured 14 days later by confocal evaluation of Griffonia simplicifolia Isolectin B4 staining of RPE–choroid flatmounts. RTP801i, inactive anti–RTP801 siRNA (negative control), PBS, VEGF–A165 aptamer (Macugen), anti–VEGF–A neutralizing antibody (Ab) or mouse IgG were injected into the vitreous on the day of injury and 7 days after the injury. For real–time RT–PCR analysis, RNA was extracted separately from RPE and sensory retina on days 1, 2, 5 and 10. The numbers of choroid infiltrating macrophages and neutrophils were assayed by flow cytometry on days 1, 3, and 12.
RTP801–/– mice displayed 30% reduction of CNV volume compared with RTP801 +/+ mice (p=0.003). RTP801i suppressed gene expression in vivo both in RPE and in sensory retina. RTP801i significantly (up to 75%) reduced CNV volume in a dose–dependent manner and to a significantly greater degree than Macugen (p=0.015) or anti–VEGF–A neutralizing Ab (p=0.016). RTP801i cooperated with anti–VEGF–A Ab and with Macugen in reducing both CNV volume and leakage. Real–time RT–PCR revealed that RTP801i significantly induced PEDF in sensory retina and reduced VEGF–A164, MIP2, MCP–1 and PKCbeta2 in RPE. RTP801i decreased maximal neutrophil and macrophage infiltration into the choroid to a significantly greater extent than either anti–VEGF–A Ab or Macugen.
RTP801i is a potentially novel strategy to inhibit CNV in AMD that displays efficacy both as monotherapy and in combination with anti–VEGF–A drugs. Its therapeutic effect may result from suppressing inflammation and angiogenic signaling as well as from promoting anti–angiogenic cytokines.
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