June 2022
Volume 63, Issue 7
Open Access
ARVO Annual Meeting Abstract  |   June 2022
Potent retinal protection by oral administration of a purine metabolite against age-related retinal degeneration and RHO-associated retinitis pigmentosa
Author Affiliations & Notes
  • Owen Clinger
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Yibo Xi
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Abhishek Vats
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Amanda Wolf-Johnson
    Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Lori Birder
    Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Edwin Jackson
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Jose Alain Sahel
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Institut de la Vision, Sorbonne Universite, Paris, Île-de-France, France
  • Yuanyuan Chen
    Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
    Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Owen Clinger None; Yibo Xi None; Abhishek Vats None; Amanda Wolf-Johnson None; Lori Birder None; Edwin Jackson None; Jose Sahel None; Yuanyuan Chen None
  • Footnotes
    Support  Bruce and Barbara Wiegand Entrepreneurial Research Award; NIH CORE Grant P30 EY08098
Investigative Ophthalmology & Visual Science June 2022, Vol.63, 1777 – F0326. doi:
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    • Get Citation

      Owen Clinger, Yibo Xi, Abhishek Vats, Amanda Wolf-Johnson, Lori Birder, Edwin Jackson, Jose Alain Sahel, Yuanyuan Chen; Potent retinal protection by oral administration of a purine metabolite against age-related retinal degeneration and RHO-associated retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1777 – F0326.

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

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Abstract

Purpose : Retinal degeneration is a common cause of vision loss, and photoreceptor loss is specifically involved in blinding diseases such as age-related macular degeneration and retinitis pigmentosa. Finding an oral agent that prevents retinal degeneration is an ideal goal for treating these diseases. The purpose of this study is to evaluate the efficacy of an oral purine metabolite as a retina protective agent in two rodent models: aged Fischer344 rats and RhoP23H/+ knock-in mice.

Methods : Aged Fischer344 rats were treated with the purine compound by supplementing the agent at 5 mg/kg in drinking water. Treatment began at 22 months of age and lasted for 8 weeks. Electroretinogram (ERG) and optical coherence tomography (OCT) were recorded at 0 and 7 weeks of treatment. Retinae were collected at 8 weeks of treatment for purine analyses, RNA-seq, immunoblots, and immunohistochemistry. Non-treated age-matched animals were used as controls. RhoP23H/+ mice were treated with 11 mg/kg of the purine metabolite beginning at postnatal day (PND) 15 by daily intraperitoneal (i.p.) injections. Drinking water for the mother of the treated litter, and subsequently the weaned pups, was also supplemented with the agent. Retinal morphology and function were evaluated weekly by ERG and OCT until the mice were sacrificed at 5 and 7 weeks of treatment. Mice treated with PBS by i. p. injections were used as vehicle controls.

Results : Eight weeks of daily oral treatment by a purine metabolite led to potent retinal protection in the Fischer344 rats at 2 years of age. This was demonstrated by thicker retinae and outer segment layers, and a higher number of nuclei in outer nuclear layer and retinal ganglion layer. Higher scotopic ERG responses were observed, suggesting improved retinal function. Rhodopsin level was significantly increased by the treatment, suggesting restored rod photoreceptor homeostasis. Systemic treatment with the same agent in RhoP23H/+ mice also showed delayed retinal degeneration and improved retinal function via OCT and ERG, respectively.

Conclusions : We discovered an oral agent that potently protects the retina against degeneration in two rodent models, thus providing a promising direction for drug development against retinal dystrophies.

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

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