June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
The role of light in the pathogenesis of rhodopsin retinitis pigmentosa
Author Affiliations & Notes
  • Rosellina Guarascio
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Kwan Hau
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Rowan Asfahani
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Kalliopi Ziaka
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Hannah Poultney
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Dimitra Athanasiou
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Monica Aguila
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Yumei Li
    Baylor College of Medicine, Houston, Texas, United States
  • Rui Chen
    Baylor College of Medicine, Houston, Texas, United States
  • Michael E Cheetham
    Institute of Ophthalmology, University College London, London, London, United Kingdom
  • Footnotes
    Commercial Relationships   Rosellina Guarascio ProQR Therapeutics, Code C (Consultant/Contractor); Kwan Hau ProQR Therapeutics, Code C (Consultant/Contractor); Rowan Asfahani ProQR Therapeutics, Code C (Consultant/Contractor); Kalliopi Ziaka ProQR Therapeutics, Code C (Consultant/Contractor); Hannah Poultney None; Dimitra Athanasiou None; Monica Aguila ProQR Therapeutics, Code E (Employment); Yumei Li None; Rui Chen None; Michael Cheetham ProQR Therapeutics, Code C (Consultant/Contractor), Alia Therapeutics, Code C (Consultant/Contractor), PYC Therapeutics, Code C (Consultant/Contractor)
  • Footnotes
    Support  Wellcome Trust Grant 538842
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 3816. doi:
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      Rosellina Guarascio, Kwan Hau, Rowan Asfahani, Kalliopi Ziaka, Hannah Poultney, Dimitra Athanasiou, Monica Aguila, Yumei Li, Rui Chen, Michael E Cheetham; The role of light in the pathogenesis of rhodopsin retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2022;63(7):3816.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Autosomal dominant Retinitis Pigmentosa (adRP) is an inherited retinal degenerative disease that initially affects rod photoreceptors function and survival. The first gene identified to cause adRP was RHO, which encodes for rhodopsin, a G-protein coupled receptor involved in the detection of low level light and the consequent activation of rods phototransduction cascade. We focused our attention on a common UK pathogenic rhodopsin amino acid substitution, RHOM39R. Here we have investigated the effect of light on retinal function and degeneration in both RHOM39R and RhoM39R models.

Methods : To investigate the role of light in retinal degeneration, we used two different models: RhoM39R knock-in (KI) mice and RHOM39R/+ human iPSC-derived retinal organoids (hROs). Different levels of light exposure were investigated as a modifier of disease. Optic Coherence Tomography (OCT) and Electroretinogram (ERG) were performed on mice to characterise mouse retina thickness and activity, respectively. Electron microscopy was performed to characterise the ultrastructure of the retina. Rhodopsin protein levels were analysed by western blotting. RNAseq was performed to evaluate changes in the retinal transcriptome, while immunohistochemistry was used to analyse rhodopsin localization and retina degeneration in both mouse retina and hROs.

Results : 3 weeks old RhoM39R/+ KI mice reared in ambient light had impaired retinal function by ERG, while the thickness of the outer nuclear layer (ONL) was comparable to control Rho+/+. By contrast, rearing in reduced ambient light exposure, protected the ERG function of RhoM39R/+ animals. Exposure to bright light (max intensity: 30 cd*s/m2) through repeated ERG, caused a progressive decrease in ONL thickness and in retinal activity. 3 week old RhoM39R/M39R KI mice raised in ambient light showed severely compromised retinal function, reduced ONL thickness and altered outer segment (OS) morphology. Moreover, a single exposure to bright light significantly decreased the ONL thickness of RhoM39R/M39R KI retina within 24h, while inducing the expression of apoptotic genes by 3h. 170-200 days old RHOM39R/+ hROs showed signs of retinal degeneration and mistrafficking of rhodopsin compared to control RHO+/+ hROs.

Conclusions : The combined study in both KI mice and human ROs can provide insights into the role of light in sector RP in mammalian models and the ability to develop new therapies to treat RP patients.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

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