June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
RETINAL EXPRESSION OF THE NF-KB INHIBITORY GENE M013 DECREASES THE RATE OF RETINAL DEGENERATION OF A GEOGRAPHIC ATROPHY MOUSE MODEL
Author Affiliations & Notes
  • Cristhian J Ildefonso
    Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States
  • Brianna Bowman Young
    Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States
  • Raela B Ridley
    Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States
  • Erin Walsh
    Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States
  • Alfred S Lewin
    Molecular Genetics & Microbiology, University of Florida, Florida, United States
    Department of Ophthalmology, University of Florida College of Medicine, Gainesville, Florida, United States
  • Footnotes
    Commercial Relationships   Cristhian Ildefonso, University of Florida Research Foundation (P); Brianna Bowman Young, None; Raela Ridley, None; Erin Walsh, None; Alfred Lewin, None
  • Footnotes
    Support  Bright Focus Grant M2017126; NEI Grant EY026268; RPB Unrestricted grant
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 4304. doi:
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      Cristhian J Ildefonso, Brianna Bowman Young, Raela B Ridley, Erin Walsh, Alfred S Lewin; RETINAL EXPRESSION OF THE NF-KB INHIBITORY GENE M013 DECREASES THE RATE OF RETINAL DEGENERATION OF A GEOGRAPHIC ATROPHY MOUSE MODEL. Invest. Ophthalmol. Vis. Sci. 2020;61(7):4304.

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

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Abstract

Purpose : Age-related macular degeneration (AMD) has been linked to inflammation and oxidative stress. We have previously demonstrated that retinal inhibition of caspase-1 with via AAV gene delivery can slow down retinal degeneration in a mouse model of geographic atrophy. This protection occurs at later stage of the mouse model. The M013 myxoma gene is known to inhibit ASC dependent activation of caspase-1 and the NF-kB nuclear translocation. Therefore, M013 not only blocks the activation of IL-1β and IL-18, but can also repress the transcription of multiple inflammatory genes. Here we provide evidence that retinal expression of the modified TatM013 can protect the retina of a geographic atrophy mouse model during early stages.

Methods : Mice of the Sod2floxed:VMD2Cre+ genotype were injected intravitreally with 1010 vector genome copies of AAV2quad(Y-F)+T491V vector delivering either sGFP or sGFP-TatM013v5 at 8 weeks of age. Mice were evaluated at 3, 6, and 9 months of age by spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG). Gliosis was detected by GFAP and Iba-1 immunofluorescence (IF). Cytokine and chemokine changes in the retina protein lysates was determined by multiplex ELISA. Changes in mRNA levels in the retina were quantified by RT-qPCR.

Results : Retinas treated with sGFP-TatM013 vector had statistically significantly higher a-, b-, and c-wave amplitudes when compared to sGFP treated eyes at the 3 and 6-months evaluations. SD-OCT evaluation demonstrated a protection of the outer segments in the sGFP-TatM013 when compared to sGFP treated eyes. Retinas expressing sGFP-TatM013 showed less GFAP and Iba-1 staining when compared to sGFP at 6 months of age. RT-qPCR studies demonstrated a significant decrease in multiple genes associated with M1 and M2 macrophages/microglia cells at 9 months of age. Finally, cytokines and chemokines were significantly altered including the neuroprotective leukemia inhibitory factor (LIF).

Conclusions : Retinal gene expression of TatM013 transiently protected the retina function of a mouse model of geographic atrophy. Treatment with TatM013 decreased gliosis, decreased the expression of inflammatory genes, and a transient increase in retinal LIF expression. Our studies suggest that targeting the NF-kB signaling locally within the retina could provide protection against AMD during early stages.

This is a 2020 ARVO Annual Meeting abstract.

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