Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sci Adv. 2024 Mar 8;10(10):eadl3576. doi: 10.1126/sciadv.adl3576.
Suprachoroidal nonviral gene therapy with biodegradable poly(β-amino ester) nanoparticles (NPs) provides widespread expression in photoreceptors and retinal pigmented epithelial (RPE) cells and therapeutic benefits in rodents. Here, we show in a human-sized minipig eye that suprachoroidal injection of 50 μl of NPs containing 19.2 μg of GFP expression plasmid caused GFP expression in photoreceptors and RPE throughout the entire eye with no toxicity. Two weeks after injection of 50, 100, or 200 μl, there was considerable within-eye and between-eye variability in expression that was reduced 3 months after injection of 200 μl and markedly reduced after three suprachoroidal injections at different locations around the eye. Reduction of bacterial sequences in the expression plasmid resulted in a trend toward higher expression. These data indicate that nonviral suprachoroidal gene therapy with optimized polymer, expression plasmid, and injection approach has potential for treating photoreceptors throughout the entire retina of a human-sized eye.
眼上腔非病毒基因治疗采用可生物降解的聚（β-氨基酸酯）纳米粒子（NPs），可在感光细胞和视网膜色素上皮（RPE）细胞中实现广泛表达，并在啮齿动物中带来治疗益处。在这里，我们在人大小猪的眼睛中显示，眼上腔注射 50 μl 含有 19.2 μg GFP 表达质粒的 NPs 可引起整个眼睛中的 GFP 表达在感光细胞和 RPE 中，且无毒性。注射后 2 周，50、100 或 200 μl 之间存在相当大的眼内和眼间表达变异性，注射 200 μl 3 个月后表达减少，在眼周围不同位置进行三次眼上腔注射后表达明显减少。表达质粒中细菌序列的减少导致表达趋势升高。这些数据表明，采用优化的聚合物、表达质粒和注射方法的非病毒眼上腔基因治疗具有治疗人大小眼整个视网膜感光细胞的潜力。
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