Zhang Xiaohui, Das Subrata K, Passi Samuel F, Uehara Hironori, Bohner Austin, Chen Marcus, Tiem Michelle, Archer Bonnie, Ambati Balamurali K
Moran Eye Center, University of Utah, Salt Lake City, Utah, USA.
Mol Ther. 2015 Feb;23(2):226-34. doi: 10.1038/mt.2014.199. Epub 2014 Oct 13.
Long-term inhibition of extracellular vascular endothelial growth factor (VEGF) in the treatment of age-related macular degeneration (AMD) may induce retinal neuronal toxicity and risk other side effects. We developed a novel strategy which inhibits retinal pigment epithelium (RPE)-derived VEGF, sparing other highly sensitive retinal tissues. Flt23k, an intraceptor inhibitor of VEGF, was able to inhibit VEGF in vitro. Adeno-associated virus type 2 (AAV2)-mediated expression of Flt23k was maintained for up to 6 months postsubretinal injection in mice. Flt23k was able to effectively inhibit laser-induced murine choroidal neovascularization (CNV). VEGF levels in the RPE/choroid complex decreased significantly in AAV2.Flt23k treated eyes. Neither retinal structure detected by Heidelberg Spectralis nor function measured by electroretinography (ERG) was adversely affected by treatment with AAV2.Flt23k. Hence AAV2.Flt23k can effectively maintain long-term expression and inhibit laser-induced CNV in mice through downregulation of VEGF while maintaining a sound retinal safety profile. These findings suggest a promising novel approach for the treatment of CNV.
长期抑制细胞外血管内皮生长因子（VEGF）治疗年龄相关性黄斑变性（AMD）可能会诱发视网膜神经元毒性并引发其他副作用。我们开发了一种新策略，可抑制视网膜色素上皮（RPE）衍生的VEGF，同时保护其他高度敏感的视网膜组织。Flt23k是一种VEGF的细胞内受体抑制剂，能够在体外抑制VEGF。在小鼠视网膜下注射后，腺相关病毒2型（AAV2）介导的Flt23k表达可维持长达6个月。Flt23k能够有效抑制激光诱导的小鼠脉络膜新生血管（CNV）。在AAV2.Flt23k治疗的眼睛中，RPE/脉络膜复合体中的VEGF水平显著降低。用AAV2.Flt23k治疗对通过海德堡光谱仪检测的视网膜结构和通过视网膜电图（ERG）测量的功能均无不利影响。因此，AAV2.Flt23k可通过下调VEGF有效维持长期表达并抑制小鼠激光诱导的CNV，同时保持良好的视网膜安全性。这些发现提示了一种有前景的治疗CNV的新方法。
