June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Efficacy of novel hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor in the prevention of retinopathy of prematurity (ROP)
Author Affiliations & Notes
  • Jin Zhang
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
    Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States
  • George Hoppe
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • John Wang
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Youstina Bolok
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Amit Sharma
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
  • Jonathan E Sears
    Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio, United States
    Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States
  • Footnotes
    Commercial Relationships   Jin Zhang, None; George Hoppe, None; John Wang, None; Youstina Bolok, None; Amit Sharma, None; Jonathan Sears, None
  • Footnotes
    Support  NIH Grant T32EY024236, NIH-NEI P30 Core Grant (IP30EY025585-01A1), Unrestricted Grant from The Research to Prevent Blindness to Cole Eye Institute, The Hartwell Foundation Individual Biomedical Research Award, and NIH NEI R01EY024972
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 3465. doi:
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      Jin Zhang, George Hoppe, John Wang, Youstina Bolok, Amit Sharma, Jonathan E Sears; Efficacy of novel hypoxia inducible factor-prolyl hydroxylase (HIF-PH) inhibitor in the prevention of retinopathy of prematurity (ROP). Invest. Ophthalmol. Vis. Sci. 2017;58(8):3465.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Small molecule HIF-PH inhibitor drugs are effective in reducing retinal ischemia and neovascularization in mouse and rat oxygen induced retinopathy (OIR) models. We evaluated the efficacy and activity profile of a novel HIF-PH inhibitor drug containing a carbonyl glycine structure common to both DMOG and roxadustat.

Methods : The mouse model of oxygen-induced retinopathy (OIR) was used to evaluate efficacy after intraperitoneal (IP) injections of 10 µg/g, 25 µg/g, and 50 µg/g drug at P6, 8, and 10 in comparison to optimized concentrations of roxadustat and DMOG. Quantification of avascular retina at P17 was used to compare the effect of each compound. Organ specific HIF-1 and HIF-2 stabilization was detected using luciferase oxygen dependent domain mouse and western blot. Induction of HIF target genes were quantified by RT-qPCR.

Results : The novel HIF-PH inhibitor significantly reduced retinal ischemia measured at P17 as compared to control at both the 25 µg/g and 50 µg/g dosages but not at 10 µg/g in the OIR model, reducing retinal avascular area by 29.9% at the 25µg/g dose (p = 0.0137) and 21.9% at the 50 µg/g dose (p = 0.0047). There was no significant difference between the 25µg/g and the 50 µg/g dose (p = 0.479). There was no significant effect seen at the 10 µg/g dose. In comparison, DMOG and roxadustat induce a 62.1% (p = 0.021) and 68.2% (p < 0.0001) decrease in avascular area at P17, respectively.

In contrast, serum erythropoietin levels increased 68.5-fold after a single injection, which was significantly higher than the 31.9-fold increase by roxadustat. Serum elevation of erythropoietin was matched by increased in vivo Epo mRNA expression which was 25-fold in the liver and 6.9-fold in the kidney. Like roxadustat, HIF-1 protein increased in retina, liver and kidney; HIF-2 was unchanged in retina and brain.

Conclusions : This novel carbonyl glycine can provide statistically significant reduction in retinal ischemia in the mouse OIR model and is especially potent in elevating serum erythropoietin.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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