June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Protective effect of pharmacological Fas inhibition in two mouse models of inherited retinal degeneration
Author Affiliations & Notes
  • Jingyu Yao
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Mengling Yang
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
    Ophthalmology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
  • Lin Jia
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Andrew J. Kocab
    ONL Therapeutics, Ann Arbor, Michigan, United States
  • David N Zacks
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Jingyu Yao None; Mengling Yang None; Lin Jia None; Andrew Kocab ONL Therapeutics, Code E (Employment), ONL Therapeutics, Code I (Personal Financial Interest), ONL Therapeutics, Code P (Patent); David Zacks ONL Therapeutics, Code C (Consultant/Contractor), ONL Therapeutics, Code F (Financial Support), ONL Therapeutics, Code I (Personal Financial Interest), ONL Therapeutics, Code P (Patent)
  • Footnotes
    Support  ONL Therapeutics; Departmental Core Grant EY-07003
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1540. doi:
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    • Get Citation

      Jingyu Yao, Mengling Yang, Lin Jia, Andrew J. Kocab, David N Zacks; Protective effect of pharmacological Fas inhibition in two mouse models of inherited retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1540.

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

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Abstract

Purpose : The large genetic heterogeneity of inherited retinal degeneration (IRD), a common cause of blinding disease in the United States, has limited the development of mutation-specific therapies, highlighting the need for therapeutic approaches targeting shared pathophysiologic pathways. The Fas receptor has been reported as a contributor to retinal cell death and inflammation in variety of ocular diseases. We previously reported the activation of Fas mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H; and demonstrated the protective effect of genetic Fas inhibition in these two mouse models. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204.

Methods : A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle solution. Fas activation was assessed by caspase 8 activity. Effect of ONL1204 on PR death was assess by TUNEL-staining, immunohistochemistry (IHC), optical coherence tomography (OCT) and Electroretinography (ERG) analysis.

Results : In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) photoreceptors and preserved thickness of the photoreceptor layer measured by OCT, consistent with increased expression of rhodopsin and cone-opsin detected by IHC. The preservation of the photoreceptor function in ONL1204 treated eyes was further confirmed by increased response of both scotopic and photopic ERG compared with vehicle treated fellow eyes.

Conclusions : The protective effect of by ONL1204 in two distinct mouse models of retinal degeneration suggests that Fas activation is a shared contributor to PR death in different IRD mutations, and that reducing Fas activity by ONL1204 represents a potential mutation-independent therapeutic approach to preserve the retina in patients with IRD.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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