Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice
Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Applewhite, Kathleen Jee, Monika Deshpande, Miguel Flores-Bellver, Ming-Wen Hu, Chuanyu Guo, Shaima Salman, Yousang Hwang, Nicole M. Anders, Michelle A. Rudek, Jiang Qian, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
Jing Zhang, Deepti Sharma, Aumreetam Dinabandhu, Jaron Sanchez, Brooks Applewhite, Kathleen Jee, Monika Deshpande, Miguel Flores-Bellver, Ming-Wen Hu, Chuanyu Guo, Shaima Salman, Yousang Hwang, Nicole M. Anders, Michelle A. Rudek, Jiang Qian, M. Valeria Canto-Soler, Gregg L. Semenza, Silvia Montaner, Akrit Sodhi
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Research Article Ophthalmology

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

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 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.

Authors

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

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Figure 10

Systemic administration of a well-tolerated dose of 32-134D inhibits HIF and HIF-regulated gene expression and effectively treats retinal vascular disease in mice.

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Systemic administration of a well-tolerated dose of 32-134D inhibits HIF...
(A) Representative fundus photos (above) and fluorescein angiographic images (below) of the retina of BL/6 mice on day 30 following 5 daily i.p. injections (day 0 to day 5) with 32-134D at 40 or 80 mg/kg compared with vehicle control. n = 3 animals (6 eyes) per group. (B) HIF-1α and HIF-2α protein accumulation at P13 and P14, respectively, 24 hours after a single i.p. injection with 32-134D (20 mg/kg) in OIR mice. (C and D) mRNA expression of HIF-regulated vasoactive mediators Vegfa, Angptl4, Pdgfb, and Epo (C) and endothelial cell genes Angpt2, Ptprb, Serpine1, and Kdr (D) in OIR mice treated with 5 consecutive (P12–P16) i.p. injections with 20 mg/kg 32-134D or vehicle control. (E) Left: representative images of retinal NV (outlined) at P17 after daily treatment with 20 mg/kg 32-134D or vehicle control (P12-16). Right: quantitation of avascular retina and retinal NV at P17. n = 3–8 animals per condition. Data are represented as mean ± SD. Statistical analyses were performed using 1-way ANOVA with Bonferroni’s multiple-comparison test (C and D) or 2-tailed Student’s t test (E). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Scale bars: 500μm.