Advertisement

ResearchIn-Press PreviewOphthalmologyTherapeutics Open Access | 10.1172/JCI163290

Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice

Jing Zhang,1 Deepti Sharma,1 Aumreetam Dinabandhu,1 Jaron Sanchez,1 Brooks Applewhite,1 Kathleen Jee,2 Monika Deshpande,2 Miguel Flores-Bellver,3 Ming-Wen Hu,2 Chuanyu Guo,2 Shaima Salman,4 Yousang Hwang,5 Nicole M. Anders,6 Michelle A. Rudek,6 Jiang Qian,2 Valeria Canto-Soler,3 Gregg L. Semenza,5 Silvia Montaner,7 and Akrit Sodhi2

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Zhang, J. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Sharma, D. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Dinabandhu, A. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Sanchez, J. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Applewhite, B. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Jee, K. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Deshpande, M. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Flores-Bellver, M. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Hu, M. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Guo, C. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Salman, S. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Hwang, Y. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Anders, N. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Rudek, M. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Qian, J. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Canto-Soler, V. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Semenza, G. in: JCI | PubMed | Google Scholar |

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Montaner, S. in: JCI | PubMed | Google Scholar

1Department of Ophthalmology, Johns Hopkins School of Medicine, Baltimore, United States of America

2Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, United States of America

3Department of Ophthalmology, University of Colorado School of Medicine, Aurora, United States of America

4Institute of Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

5Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, United States of America

6Department of Oncology, Johns Hopkins University, Baltimore, United States of America

7Department of Oncology and Diagnostic Sciences, University of Maryland, Baltimore, United States of America

Find articles by Sodhi, A. in: JCI | PubMed | Google Scholar |

Published May 25, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI163290.
Copyright © 2023, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 25, 2023 - Version history
View PDF
Abstract

Many patients with diabetic eye disease respond inadequately to anti-VEGF therapies, implicating additional vasoactive mediators in its pathogenesis. We demonstrate that levels of angiogenic proteins regulated by hypoxia-inducible factor (HIF)-1 and -2 (HIFs) remain elevated in diabetic eyes despite treatment with anti-VEGF therapy. Conversely, by inhibiting HIFs we normalized the expression of multiple vasoactive mediators in mouse models of diabetic eye disease. Accumulation of HIFs and HIF-regulated vasoactive mediators in hyperglycemic animals was observed in the absence of tissue hypoxia, suggesting that targeting HIFs may be an effective early treatment for diabetic retinopathy. However, while the HIF-inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients. Conversely, 32-134D, a recently developed HIF inhibitor structurally unrelated to acriflavine, was not toxic to the retina, yet effectively inhibited HIF accumulation and normalized HIF-regulated gene expression in mice and in human retinal organoids. Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.

Graphical Abstract
graphical abstract
Supplemental material

View

View Supplemental Figures 1 to 5

Version history
  • Version 1 (May 25, 2023): In-Press Preview
Advertisement
Advertisement