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Jonathan E Sears, Suzy Yoon, Rebecca Brown, Kelsey Case, George Hoppe, ; Pharmacological Stabilization of Hypoxia Inducible Factor 1 by FG 4592 Prevents Oxygen Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3634.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: We have previously reported that dimethyl oxaloylglycine (DMOG) induced hypoxia inducible factor 1 (HIF-1) stabilization in the liver prevents oxygen-induced retinopathy (OIR). We have further identified novel isoquinolones and hydrazones that are potent HIF stabilizers. Here we test FG-4592, an isoquinolone currently in phase III clinical trials in adults with anemia from chronic kidney disease, in the mouse OIR model.
The luciferase-oxygen dependent domain (luc-ODD) mouse was used to localize FG-4592 activity in the whole animal. Time and dose response experiments were performed to analyze endogenous HIF stabilization as well as HIF target Epo in vivo and in vitro. OIR experiments followed by retinal flat mount analysis were used to compare the effect of DMOG vs FG-4592. Reduction of hyperoxia-induced ischemia was measured using Hypoxyprobe. RNA-seq experiments were performed with liver RNA to evaluate possible secreted hepatokines that might mediate the protective effect of FG-4592. Secondary validation of hepatokines was performed by RT-qPCR and measurement of serum and tissue protein by ELISA and Western blot.
The luc-ODD mouse demonstrated that FG-4592 targets both the liver and kidney with sustained HIF stabilization over 24 hours. Dose response experiments demonstrated that 10 ug/g BW induced maximal expression of Epo without toxicity. This dose also reduced capillary drop out three-fold in the OIR model. RNA seq demonstrated 3-fold induction of angiopoietin like protein 3 (Angptl3, p= 0.009). Secondary validation by RT-PCR confirmed increased Angptl3 expression in liver. Serum values of Angptl3 increase at 6 hours and reached maximal immunoreactivity at 24 hours.
FG-4592 prevents OIR more efficiently than DMOG and at a lower dose. The optimal dose in mice is comparable to the dose used in human trials. FG-4592, like DMOG, prevents ischemia by protecting vasculature from hyperoxia induced vasoobliteration. Angptl3 is a reliable surrogate biomarker of treatment effect.
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