C型利钠肽治疗青光眼性视神经损伤的实验研究

The pathological basis of glaucoma is retinal ganglion cell (RGC) apoptosis. Lowering the intraocular pressure (IOP) is the major management of glaucoma. Currently, no effective optic nerve protections exist. The preliminary work of our group showed that the C-type natriuretic peptide (CNP) had protective effect against retinal ganglion cell apoptosis. In addition, CNP could also lower intraocular pressure by reducing aqueous humor production. However, in order to maintain therapeutic effect, natriuretic peptide needs to be repeatedly administered due to the fact that it is susceptible to neutral peptide enzymatic hydrolysis. Moreover, due to poor corneal/conjunctiva permeability of the natriuretic peptide, CNP can only be delivered into the eye through repeated intraocular injection, which is not clinically practical. To solve these problems, our group intend to use gene therapy and hydrogel approaches to study the neuroprotective effect of CNP on glaucomatous optic nerve damage. First, monkey optic nerve damage model is established based on previous rat excitotoxic retinopathy model；second, CNP lentiviral vector or hydrogel/CNP were delivered into monkey eyes intravitreally. The neuroprotective effect of CNP on retinal ganglion cell damage and intraocular pressure-lowering effect will be observed. This study will lay the foundation for the treatment of glaucoma by natriuretic peptide. We strive to achieve a breakthrough in the treatment of this second major human blindness disease.

青光眼的病理基础是视网膜神经节细胞凋亡，而目前青光眼的治疗仅以降眼压为主而缺乏有效的视神经保护方法。课题组前期工作表明，C-型利钠肽（C-type natriuretic peptide，CNP）有明显的视网膜神经节细胞保护作用，CNP还可以通过减少房水生成降眼压。但CNP的角膜/结膜通透性差，只能通过眼内注射给药；且在眼内CNP易被中性内肽酶水解而需反复给药以维持有效浓度；而反复的眼内注射无临床意义。本课题拟用CNP基因表达和水凝胶缓释CNP蛋白的两种方法研究CNP对视网膜神经节细胞的保护作用。在前期大鼠模型的基础上，用兴奋性氨基酸诱导猴青光眼性视神经损伤；用慢病毒载体/水凝胶缓释系统将CNP基因/蛋白一次性导入猴眼玻璃体腔内，观察CNP对视网膜神经节细胞的保护及降眼压作用，为CNP治疗青光眼的临床应用打下基础，争取在人类第二大致盲眼病青光眼的治疗上有所突破。

青光眼的病理基础是视网膜神经节细胞凋亡，而目前青光眼的治疗仅以降眼压为主而缺乏有效的视神经保护方法。课题组前期工作表明，C-型利钠肽（C-type natriuretic peptide，CNP）有明显的视网膜神经节细胞保护作用，CNP还可以通过减少房水生成降眼压。本课题通过筛选青光眼基因治疗的载体，包括rAAV病毒载体和LV病毒载体，最终筛选出LV介导CNP进行基因治疗的理想体系，构建了CNP病毒载体，分别通过兴奋性氨基酸视神经损伤和急性高眼压动物模型，证实CNP 的视神经保护作用，并有效地建立了CNP治疗青光眼的研究平台，同时，也研究了另一小分子蛋白质，即外酶C3转移酶（C3），发现其有更为确切的降眼压和神经保护作用。本研究通过评估CNP以及C3的视神经保护及降眼压作用，为治疗青光眼的临床应用打下了基础，在人类第二大致盲眼病青光眼的治疗上有所突破。.