Ablating VHL in Rod Photoreceptors Modulates RPE Glycolysis and Improves Preclinical Model of Retinitis Pigmentosa

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

doi:10.1172/JCI185796

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

Find articles by Cui, X. in: JCI | PubMed | Google Scholar

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

Find articles by Lopes da Costa, B. in: JCI | PubMed | Google Scholar

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

Find articles by Quinn, P. in: JCI | PubMed | Google Scholar |

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

¹Department of Biomedical Engineering, Columbia University, New York, United States of America

²Ophthalmology, Columbia University, New York, United States of America

³Department of Biochemistry, University of Washington, Seattle, United States of America

⁴Jonas Children's Vision Care and Bernard & Shirlee Brown Glaucoma Laborator, Columbia University, New York, United States of America

⁵Department of Ophthalmology and Visual Sciences, West Virginia University, Morgantown, United States of America

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

J Clin Invest. https://doi.org/10.1172/JCI185796.
Copyright © 2025, Caruso 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 February 12, 2025 - Version history

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, non-cell-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.

Version 1 (February 12, 2025): In-Press Preview

Ablating VHL in Rod Photoreceptors Modulates RPE Glycolysis and Improves Preclinical Model of Retinitis Pigmentosa

Salvatore Marco Caruso,¹ Xuan Cui,² Brian M. Robbings,³ Noah Heaps,⁴ Aykut Demikrol,² Bruna Lopes da Costa,¹ Daniel T. Hass,³ Peter M.J. Quinn,⁴ Jianhai Du,⁵ James B. Hurley,³ and Stephen H. Tsang¹

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Ablating VHL in Rod Photoreceptors Modulates RPE Glycolysis and Improves Preclinical Model of Retinitis Pigmentosa

Salvatore Marco Caruso,1 Xuan Cui,2 Brian M. Robbings,3 Noah Heaps,4 Aykut Demikrol,2 Bruna Lopes da Costa,1 Daniel T. Hass,3 Peter M.J. Quinn,4 Jianhai Du,5 James B. Hurley,3 and Stephen H. Tsang1

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Salvatore Marco Caruso,¹ Xuan Cui,² Brian M. Robbings,³ Noah Heaps,⁴ Aykut Demikrol,² Bruna Lopes da Costa,¹ Daniel T. Hass,³ Peter M.J. Quinn,⁴ Jianhai Du,⁵ James B. Hurley,³ and Stephen H. Tsang¹