June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
A novel non-retinoid visual cycle inhibitor RPE65-61 protects the retinal photoreceptors from light-induced degeneration
Author Affiliations & Notes
  • Gennadiy P Moiseyev
    Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Yuhong Wang
    Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Xiang Ma
    Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Parthasarathy Muthuraman
    Departments of Basic & Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, United States
  • Arun Raja
    Departments of Basic & Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, United States
  • Aravindan Jayaraman
    Departments of Basic & Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, United States
  • Konstantin Petrukhin
    Ophthalmology, Columbia University, New York, New York, United States
  • Christopher Cioffi
    Departments of Basic & Clinical Sciences and Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, United States
  • Jian-Xing Ma
    Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
  • Footnotes
    Commercial Relationships   Gennadiy Moiseyev None; Yuhong Wang None; Xiang Ma None; Parthasarathy Muthuraman None; Arun Raja None; Aravindan Jayaraman None; Konstantin Petrukhin None; Christopher Cioffi None; Jian-Xing Ma None
  • Footnotes
    Support  NIH grants EY019309, EY012231, EY032930, EY028949, and GM122744
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1773 – F0322. doi:
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      Gennadiy P Moiseyev, Yuhong Wang, Xiang Ma, Parthasarathy Muthuraman, Arun Raja, Aravindan Jayaraman, Konstantin Petrukhin, Christopher Cioffi, Jian-Xing Ma; A novel non-retinoid visual cycle inhibitor RPE65-61 protects the retinal photoreceptors from light-induced degeneration. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1773 – F0322.

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

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Abstract

Purpose : The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal neuron survival. Unfortunately, during the visual cycle, when 11-cis-retinal is being regenerated in the retina, toxic byproducts, such as all-trans-retinal and bis-retinoid such as N-retinylidene-N-retinylethanolamine (A2E), are produced, which contributes to the pathogenesis of dry form of age-related macular degeneration (AMD) and Stargardt’s disease (STGD). To prevent all-trans-retinal mediated retinal degeneration, slowing down the retinoid flow by inhibiting the visual cycle with a small molecule was proposed. The present study describes RPE65-61, a novel, non-retinoid compound, as an inhibitor of RPE65 intended to modulate the excessive activity of the visual cycle to protect the retina from degenerative diseases.

Methods : To determine the inhibition mode of the RPE65-61, we used an adenoviral vector to express chicken RPE65 in 293A cells, and the chicken RPE65 was used in a liposome-based isomerase assay. One hour after the systemic administration of RPE65-61 or vehicle, mice were placed in a light box with white fluorescent tube lights (10,000 lux for 3 hr). The mice were returned to regular housing for five days, and then the light-induced retinal damage (LIRD) was assessed using histology and ERG. Retinoid profiles recovery after the photobleach was assayed using HPLC.

Results : RPE65-61 selectively inhibited retinoid isomerase activity of RPE65 via an uncompetitive mechanism, with IC50 of 80 nM. Systemic treatment of mice with RPE65-61 resulted in slower chromophore regeneration after the photobleach and protected the retina from LIRD. Furthermore, RPE65-61 down-regulated the cyclic GMP-AMP synthase stimulator of the interferon genes pathway, decreased the inflammatory factor, attenuated retinal apoptosis caused by LIRD, which led to the preservation of the retinal function.

Conclusions : RPE65-61 potently and selectively inhibited conversion of all-trans-retinyl ester to 11-cis-retinol catalyzed by RPE65. Mice injected with RPE65-61 exhibited delayed chromophore regeneration after photobleach and conferred protection of retina against LIRD. Taken together, these results suggest that RPE65-61 may be used to slow down the visual cycle and to prevent the accumulation of A2E in STGD and AMD.

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

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