Gene Delivery of a Caspase Activation and Recruitment Domain Improves Retinal Pigment Epithelial Function and Modulates Inflammation in a Mouse Model with Features of Dry Age-Related Macular Degeneration
| Autor: | Choudhary, Mayur, Ildefonso, Cristhian J., Lewin, Alfred S., Malek, Goldis |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | J Ocul Pharmacol Ther |
| ISSN: | 1557-7732 1080-7683 |
| Popis: | PURPOSE: The NLRP3 inflammasome, a cytoplasmic signal transduction complex that regulates inflammation, has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of visual impairment in industrialized countries. We tested the therapeutic effect of anti-inflammatory gene therapy, delivered preventively, in Liver-X-Receptor alpha knockout (LXRα(−/−)) mice, which exhibit features of dry AMD. METHODS: LXRα(−/−) mice were treated with an adeno-associated virus (AAV) vector that delivers a secretable and cell-penetrating form of the caspase activation and recruitment domain (CARD). A sGFP-FCS-TatCARD-AAV or sGFP-FCS (control) vector was delivered intravitreally to 3–5 month-old, LXRα(−/−) mice, who were then aged to 15–18 months (12–13 month treatment). Retinal function and morphology were assessed pre- and post-treatment. RESULTS: TatCARD treated LXRα(−/−) mice did not show improvement in rod and cone photoreceptor function, measured by dark adapted a- and b-wave amplitudes, and rod-saturated b-wave amplitudes. We found a sex-dependent, significant therapeutic effect in c-wave amplitudes in the TatCARD treated mice, which exhibited maintenance of amplitudes in comparison to the significant decline recorded in the control treated group, indicating a therapeutic effect mediated in part through retinal pigment epithelial (RPE) cells. Additionally, the retinas of the TatCARD treated mice exhibited a significant decline in the concentration of interleukin-1 beta (IL-1β) concomitant with modulation of several inflammatory cytokines in the retina and RPE-choroid tissues, as measured by ELISA and cytokine array, respectively. CONCLUSION: Collectively, these results support that anti-inflammatory gene constructs such as AAV-TatCARD may be considered for the treatment of inflammation in AMD and other ocular diseases of the posterior pole in which inflammation may play a role. Furthermore, our findings emphasize the need to carefully consider potential sex-different responses when assessing potential therapies in pre-clinical models. |
| Databáze: | OpenAIRE |
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