Wang Xingxing, Lin Jun, Arzeno Alexander, Choi Jin Young, Boccio Juliann, Frieden Eric, Bhargava Ajay, Maynard George, Tsai James C, Strittmatter Stephen M
Program in Cellular Neuroscience, Neurodegeneration & Repair, Yale University School of Medicine, New Haven, Connecticut, United States Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, United States.
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut, United States.
Invest Ophthalmol Vis Sci. 2015 Feb 5;56(2):1357-66. doi: 10.1167/iovs.14-15472.
Glaucoma is a major cause of vision loss due to retinal ganglion cell (RGC) degeneration. Therapeutic intervention controls increased IOP, but neuroprotection is unavailable. NogoReceptor1 (NgR1) limits adult central nervous system (CNS) axonal sprouting and regeneration. We examined NgR1 blocking decoy as a potential therapy by defining the pharmacokinetics of intravitreal NgR(310)-Fc, its promotion of RGC axonal regeneration following nerve crush, and its neuroprotective effect in a microbead glaucoma model.
Human NgR1(310)-Fc was administered intravitreally, and levels were monitored in rat vitreal humor and retina. Axonal regeneration after optic nerve crush was assessed by cholera toxin β anterograde labeling. In a microbead model of glaucoma with increased IOP, the number of surviving and actively transporting RGCs was determined after 4 weeks by retrograde tracing with Fluro-Gold (FG) from the superior colliculus.
After intravitreal bolus administration, the terminal half-life of NgR1(310)-Fc between 1 and 7 days was approximately 24 hours. Injection of 5 μg protein once per week after optic nerve crush injury significantly increased RGCs with regenerating axons. Microbeads delivered to the anterior chamber increased pressure, and caused 15% reduction in FG-labeled RGCs of control rats, with a 40% reduction in large diameter RGCs. Intravitreal treatment with NgR1(310)-Fc did not reduce IOP, but maintained large diameter RGC density at control levels.
Human NgR1(310)-Fc has favorable pharmacokinetics in the vitreal space and rescues large diameter RGC counts from increased IOP. Thus, the NgR1 blocking decoy protein may have efficacy as a disease-modifying therapy for glaucoma.
青光眼是视网膜神经节细胞（RGC）退化导致视力丧失的主要原因。治疗干预可控制眼压升高，但神经保护治疗尚不可用。Nogo受体1（NgR1）限制成年中枢神经系统（CNS）轴突的发芽和再生。我们通过确定玻璃体内NgR(310)-Fc的药代动力学、其在神经挤压后对RGC轴突再生的促进作用以及在微珠青光眼模型中的神经保护作用，研究了NgR1阻断诱饵作为一种潜在治疗方法的效果。
将人NgR1(310)-Fc玻璃体内给药，并在大鼠玻璃体液和视网膜中监测其水平。通过霍乱毒素β顺行标记评估视神经挤压后的轴突再生。在眼压升高的青光眼微珠模型中，4周后通过从上丘逆行注射荧光金（FG）追踪来确定存活和活跃运输的RGC数量。
玻璃体内大剂量给药后，1至7天内NgR1(310)-Fc的终末半衰期约为24小时。视神经挤压损伤后每周注射一次5μg蛋白质可显著增加具有再生轴突的RGC数量。注入前房的微珠可升高眼压，并使对照大鼠中FG标记的RGC减少15%，大直径RGC减少40%。玻璃体内注射NgR1(310)-Fc并未降低眼压，但可将大直径RGC密度维持在对照水平。
人NgR1(310)-Fc在玻璃体空间具有良好的药代动力学，并可挽救因眼压升高而减少的大直径RGC数量。因此，NgR1阻断诱饵蛋白可能作为一种改善病情的青光眼治疗方法具有疗效。
