青光眼的基因治疗：现状与挑战

原发性青光眼是受环境因素影响的多基因复杂遗传病，针对青光眼的基因治疗策略尚不能仅单纯使用针对单一致病基因进行矫正或补偿，但目前基因疗法仍可显示出积极的延缓发病、减轻或改善症状等“治标”结果。目前的青光眼基因治疗策略包括以增加房水排出为主的靶向小梁网的细胞骨架调节蛋白及靶向葡萄膜巩膜房水排出通道的基因疗法，以及以减少房水生成为主的针对睫状体上皮的基因疗法等。此外还有滤过性手术后抗瘢痕的基因疗法（如术后将基质金属蛋白酶3基因转入术区表达）、视网膜神经保护基因疗法在内层视网膜表达脑源性神经营养因子、激活神经营养素受体等而改善视网膜神经节细胞（RGC）营养，外源表达抗凋亡基因产物以拮抗RGC凋亡，免疫调节减轻RGC凋亡，调节胶质细胞功能支持RGC，减少氧化应激活性氧抗RGC凋亡等]。但目前的病毒载体仍有一定几率的风险性，通过改造转基因载体使其实现精准、特异的靶向表达是一种有效解决办法，这也是推动青光眼基因疗法技术实用化的关键。此外，如何能维持长效表达增加有效治疗期也是青光眼基因治疗面临的挑战。（眼科，2022，31： 1-7）

Gene therapy targeting glaucoma: reality and challenge

Primary glaucoma is a kind of multigenic complex hereditary disease affected by environmental factors. The gene therapy strategy for glaucoma can not correct or compensate for a single pathogenic gene only, but at present, gene therapy can still show “palliative” results such as actively delaying the onset, reducing or releasing symptoms. The current gene therapy strategies for glaucoma include gene therapy targeting the cytoskeleton regulatory protein of trabecular meshwork, gene therapy targeting the uveoscleral aqueous humor outflow channel, both of which mainly increase aqueous humor outflow and gene therapy targeting the ciliary epithelium, which mainly reduces aqueous humor production. In addition, anti-cicatricial gene therapy after trabecular surgery (such as transducing the metalloproteinase-3 gene into the operation area), retinal neuroprotective gene therapy including improvement of retinal ganglion cell (RGC) nutrition by expressing brain-derived neurotrophic factor and activating neurotrophin receptor in the inner retina, exogenous expression of anti-apoptotic gene factors to antagonize RGC apoptosis, immune regulation to reduce RGC apoptosis, regulating glial cell function to support RGC, reducing reactive oxygen species (ROS), to antagonize RGC apoptosis, etc.]. However, the viral vectors still show risks more or less. It is an effective solution modifying the transgenic vectors to achieve accurate and specific targeted expression, which is also the key to promote the practicability of glaucoma gene therapy technology. In addition, how to maintain long-term expression and increase the effective therapeutic period is also a challenge for glaucoma gene therapy. (Ophthalmol CHN, 2022, 31: 1-7)