视网膜色素上皮 (RPE) 65 是视觉循环中参与 11-顺式视网膜再生的关键酶。人类 RPE65 基因突变会导致莱伯氏先天性黑蒙 (LCA)，这是一种严重的遗传性视网膜疾病。携带 Rpe65 突变的动物模型会出现早发性视网膜变性。特别是，视锥细胞比视杆细胞退化得更快。迄今为止，基因疗法已成功用于治疗 RPE65 相关的视网膜疾病。然而，基因治疗并不能完全预防患者进行性视网膜变性，这可能是由于这些患者的视锥细胞脆弱性所致。在本研究中，我们测试了白血病抑制因子（LIF）（一种营养因子）是否可以保护 Rpe65 中存在无义突变的 rd12 小鼠的视锥细胞。通过玻璃体内显微注射将 LIF 给予 rd12 小鼠。通过TUNEL测定分析视网膜细胞的凋亡。通过视网膜切片和视网膜平板的免疫染色评估视锥细胞的变性。通过免疫印迹法测定视网膜和培养细胞中LIF调节的信号蛋白。玻璃体内注射LIF激活STAT3信号通路，从而抑制rd12小鼠的光感受器凋亡并保护视锥细胞。 Niclosamide (NCL) 是一种 STAT3 信号传导抑制剂，可有效阻断经 LIF 处理的培养 661W 细胞中的 STAT3 信号传导和自噬。 LIF 与 NCL 共同给予 rd12 小鼠，消除了 LIF 的保护作用，表明 STAT3 信号传导和自噬介导了这种保护作用。LIF 是保护 rd12 小鼠视锥细胞的有效因子。这一发现意味着 LIF 可以与基因治疗结合使用，为 RPE65 相关 LCA 患者取得更好的治疗结果。版权所有 © Bentham Science Publishers；如有任何疑问，请发送电子邮件至 epub@benthamscience.net。

Retinal pigment epithelium (RPE) 65 is a key enzyme in the visual cycle involved in the regeneration of 11-cis-retinal. Mutations in the human RPE65 gene cause Leber's congenital amaurosis (LCA), a severe form of an inherited retinal disorder. Animal models carrying Rpe65 mutations develop early-onset retinal degeneration. In particular, the cones degenerate faster than the rods. To date, gene therapy has been used successfully to treat RPE65-associated retinal disorders. However, gene therapy does not completely prevent progressive retinal degeneration in patients, possibly due to the vulnerability of cones in these patients. In the present study, we tested whether leukemia inhibitory factor (LIF), a trophic factor, protects cones in rd12 mice harboring a nonsense mutation in Rpe65.LIF was administrated to rd12 mice by intravitreal microinjection. Apoptosis of retinal cells was analyzed by TUNEL assay. The degeneration of cone cells was evaluated by immunostaining of retinal sections and retinal flat-mounts. Signaling proteins regulated by LIF in the retinal and cultured cells were determined by immunoblotting.Intravitreal administration of LIF activated the STAT3 signaling pathway, thereby inhibiting photoreceptor apoptosis and preserving cones in rd12 mice. Niclosamide (NCL), an inhibitor of STAT3 signaling, effectively blocked STAT3 signaling and autophagy in cultured 661W cells treated with LIF. Co-administration of LIF with NCL to rd12 mice abolished the protective effect of LIF, suggesting that STAT3 signaling and autophagy mediate the protection.LIF is a potent factor that protects cones in rd12 mice. This finding implies that LIF can be used in combination with gene therapy to achieve better therapeutic outcomes for patients with RPE65-associated LCA.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.