Young Brianna M, Jones Kyle, Massengill Michael T, Walsh Erin, Li Hong, Lewin Alfred S, Ildefonso Cristhian J
Department of Ophthalmology, University of Florida College of Medicine, Gainesville, FL 32610-0284, USA.
Department of Molecular Genetics & Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
Mol Ther Methods Clin Dev. 2019 Jun 12;14:113-125. doi: 10.1016/j.omtm.2019.06.001. eCollection 2019 Sep 13.
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 ), 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.
年龄相关性黄斑变性（AMD）与氧化损伤和准炎症有关，后者是视网膜色素上皮（RPE）和下方脉络膜毛细血管中炎性小体信号的激活。在此，我们测试了基因递送的半胱天冬酶-1抑制剂在控制RPE-脉络膜氧化损伤的两种模型中观察到的视网膜变性方面的疗效。在氧化应激急性模型（注射碘酸钠）中，与对照处理的眼睛相比，用sGFP-TatCARD（转录激活因子；半胱天冬酶激活和募集结构域）载体预处理的眼睛在损伤后1个月显示出视网膜功能的恢复和RPE结构的部分保护。在慢性氧化应激模型（RPE特异性缺失）中，与对照处理的眼睛相比，变性开始后用sGFP-TatCARD载体处理的眼睛视网膜功能下降明显较慢。与对照处理的眼睛相比，用相同的腺相关病毒（AAV）载体对该模型进行早期治疗，在用TatCARD处理的眼睛中对RPE功能有更大的保护作用。我们的结果表明，玻璃体内递送sGFP-TatCARD可减轻炎症，并可保护视网膜免受RPE和脉络膜内急性和持续性氧化损伤。因此，用细胞穿透性炎性小体抑制剂如CARD进行基因治疗可能会阻止AMD的进展。
