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

Autor: Zhang J; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, China., Sharma D; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Dinabandhu A; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.; Department of Oncology and Diagnostic Sciences, School of Dentistry, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA., Sanchez J; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Applewhite B; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Jee K; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Deshpande M; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Flores-Bellver M; CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, Colorado, USA., Hu MW; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Guo C; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Salman S; Armstrong Oxygen Biology Research Center; Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Hwang Y; Armstrong Oxygen Biology Research Center; Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Anders NM; The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology and the Division of Clinical Pharmacology at the School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Rudek MA; The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology and the Division of Clinical Pharmacology at the School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA., Qian J; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Canto-Soler MV; CellSight Ocular Stem Cell and Regeneration Research Program, Department of Ophthalmology, Sue Anschutz-Rodgers Eye Center, University of Colorado School of Medicine, Aurora, Colorado, USA., Semenza GL; Armstrong Oxygen Biology Research Center; Vascular Program, Institute for Cell Engineering; Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, Biological Chemistry, and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Montaner S; Department of Oncology and Diagnostic Sciences, School of Dentistry, Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA., Sodhi A; Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2023 Jul 03; Vol. 133 (13). Date of Electronic Publication: 2023 Jul 03.
DOI: 10.1172/JCI163290
Abstrakt: 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 HIF-1 and -2 remain elevated in the eyes of people with diabetes 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.
Databáze: MEDLINE