Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa
Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang
Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang
Published February 12, 2025
Citation Information: J Clin Invest. 2025;135(7):e185796. https://doi.org/10.1172/JCI185796.
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Research Article Metabolism Ophthalmology

Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa

Abstract

Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, noncell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.

Authors

Salvatore Marco Caruso, Xuan Cui, Brian M. Robbings, Noah Heaps, Aykut Demirkol, Bruna Lopes Da Costa, Daniel T. Hass, Peter M.J. Quinn, Jianhai Du, James B. Hurley, Stephen H. Tsang

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Figure 1

Rod-specific VHL ablation improves both rod and cone function in the Pde6bH620Q/H620Q mutant background.

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Rod-specific VHL ablation improves both rod and cone function in the Pde...
Cre-inducible treated (Vhl–/–; Pde6bH620Q/H620Q; Pde6gCre–ERT2/+) and untreated (VhlloxP/loxP; Pde6bH620Q/H620Q; Pde6gCre–ERT2/+) mice were subjected to functional and histological analyses that demonstrated meaningful rescue. (A) Representative schematic of histological cross sections from treated and untreated eyes is shown. (B) Quantification of retinal thickness as a distance from optic nerve as measured from histological sections (n ≥ 5). A 2-tailed t test was performed to determine significance. (C) Representative traces of treated (pink) and control (black) mice at each timepoint for each phase are provided. ERG analysis consisted of 3 phases: a dark-adapted phase in which the rod-specific responses were studied, a maximum response where full retinal signaling occurs, and a cone-specific response in which the rods are photobleached. (D) ERG responses of 4-, 6-, and 8-week-old mice (n ≥ 6). An average across the eyes was taken for each mouse and treated as n = 1. A 2-tailed t test was performed to determine significance. All Error bars shown represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.