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Mol Ther Methods Clin Dev. 2019 Jun 12;14:113-125. doi: 10.1016/j.omtm.2019.06.001. eCollection 2019 Sep 13.

Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model.

Author information

1
Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610-0284, USA.
2
Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.

Abstract

Age-related macular degeneration (AMD) has been linked to oxidative damage and para-inflammation, an activation of inflammasome signaling in the retinal pigment epithelium (RPE) and the underlying choriocapillaris. Herein, we tested the efficacy of a gene-delivered caspase-1 inhibitor in controlling the retinal degeneration observed in two models of RPE-choroid oxidative damage. In an acute model of oxidative stress (NaIO3 injection), eyes pre-treated with the sGFP-TatCARD (trans-activator of transcription; caspase activation and recruitment domain) vector demonstrated a recovery of retinal function and partial protection of RPE structure 1 month after damage, in contrast with control-treated eyes. In a model of chronic oxidative stress (RPE-specific deletion of Sod2), eyes treated with the sGFP-TatCARD vector after the onset of degeneration had a significantly slower decline in retinal function when compared to control-treated eyes. Earlier treatment of this model with the same adeno-associated virus (AAV) vector resulted in a greater protection of RPE function in eyes treated with the TatCARD when compared to control-treated eyes. Our results demonstrate that intravitreal delivery of sGFP-TatCARD reduces inflammation and can protect the retina from both acute and sustained oxidative damage within the RPE and choroid. Therefore, gene therapy with a cell-penetrating inflammasome inhibitor such as CARD may stem the progression of AMD.

KEYWORDS:

adeno-associated virus; caspase-1; inflammation; interleukin-1 beta; retina

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