Inhibiting HIF-1 and its Downstream RPE Products: A Novel Therapeutic Avenue for Choroidal Neovascularization in Age-Related Macular Degeneration

Increased expression of HIF-1α in retinal pigment epithelium (RPE) cells subjected to oxidative stress promotes choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD), while inadequate HIF-1α expression in photoreceptors contributes to the development of geographic atrophy (GA), according to a study published in PNAS.

“Using a combination of cell-based models, human induced pluripotent stem cell–derived RPE and retinal organoids, as well as animal models for ocular oxidative stress, we examine the relationship among oxidative stress, hypoxia, and the accumulation of HIF-1α in RPE and retinal photoreceptors and identify key molecular events that contribute to the development of both CNV and GA,” wrote Savalan Babapoor-Farrokhran, Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins School of Medicine in Baltimore, MD, and co-authors.

Examination of eyes from patients with advanced AMD showed an increased expression in the RPE of the antioxidant enzyme thioredoxin, indicating an increase in the RPE response to oxidative stress. Additionally, the acute dose- and time-dependent production of reactive oxygen species (ROS) was found in cultured immortalized RPE cell lines in supraphysiologic doses of tert-butyl hydroperoxide. The study also showed that HIF-1α is necessary for hypoxia and oxidative stress to promote the expression of angiogenic mediators by RPE cells.

In an animal model of ocular oxidative stress, blocking the expression of angiogenic mediators through HIF-1 inhibition prevented CNV development. This demonstrates the detrimental role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. Human-induced pluripotent stem cell (hiPSC)-derived RPE cells were resistant to oxidative stress, while hiPSC-derived retinal photoreceptors were apoptosis-prone when exposed to the same chemical oxidants. In two mouse models for oxidative stress, pharmacologic inhibition of HIF-1 in the retina enhanced photoreceptor apoptosis, while HIF-1 augmentation reduced it, suggesting a protective role for HIF-1 in photoreceptors of patients with advanced dry AMD.

“Collectively, these results suggest that inhibition of HIF-1 and the expression of HIF-regulated gene products by RPE cells may be an effective approach for the treatment or prevention of nvAMD,” concluded the study authors.

Reference

Babapoor-Farrokhran S, Qin Y, Flores-Bellver M, et al. Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration. Proc Natl Acad Sci U S A. 2023;120(50):e2302845120. doi:10.1073/pnas.2302845120