Expression of a CARD Slows the Retinal Degeneration of a Geographic Atrophy Mouse Model
Brianna M Young1, Kyle Jones2, Michael T Massengill2
1Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610-0284, USA.
Insights
Gene therapy using a caspase-1 inhibitor protected against retinal degeneration caused by oxidative stress. This approach may offer a new treatment for age-related macular degeneration (AMD).
Area of Science:
- Ophthalmology
- Molecular Biology
- Gene Therapy
Background:
- Age-related macular degeneration (AMD) involves oxidative damage and inflammation in the retina.
- Inflammasome signaling in the retinal pigment epithelium (RPE) and choriocapillaris contributes to AMD pathogenesis.
- Oxidative stress is a key factor in RPE and choroid degeneration.
Purpose of the Study:
- To evaluate the efficacy of a gene-delivered caspase-1 inhibitor in controlling retinal degeneration.
- To assess the protective effects of the sGFP-TatCARD vector against oxidative damage in AMD models.
- To determine if gene therapy can mitigate inflammation and protect RPE and choroid.
Main Methods:
- Utilized two models of RPE-choroid oxidative damage: acute (NaIO3 injection) and chronic (RPE-specific Sod2 deletion).
- Administered adeno-associated virus (AAV) vectors delivering sGFP-TatCARD (a caspase-1 inhibitor) via intravitreal injection.
- Assessed retinal function and RPE structure recovery/protection post-treatment.
Main Results:
- Pre-treatment with sGFP-TatCARD in the acute model led to retinal function recovery and partial RPE protection.
- Treatment after degeneration onset in the chronic model significantly slowed retinal function decline.
- Earlier AAV vector treatment in the chronic model provided greater RPE function protection compared to controls.
Conclusions:
- Intravitreal delivery of sGFP-TatCARD effectively reduces retinal inflammation and protects against oxidative damage.
- Gene therapy with a cell-penetrating inflammasome inhibitor shows potential for halting AMD progression.
- Targeting caspase-1 with gene therapy offers a promising strategy for AMD treatment.
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.
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