PDF(Pubmed)
Abstract：
The alternative pathway of the complement system is implicated in the etiology of age-related macular degeneration (AMD). Complement depletion with pegcetacoplan and avacincaptad pegol are FDA-approved treatments for geographic atrophy in AMD that, while effective, have clinically observed risks of choroidal neovascular (CNV) conversion, optic neuritis, and retinal vasculitis, leaving room for other equally efficacious but safer therapeutics, including Poly Sialic acid (PSA) nanoparticle (PolySia-NP)-actuated complement factor H (CFH) alternative pathway inhibition. Our previous paper demonstrated that PolySia-NP inhibits pro-inflammatory polarization and cytokine release. Here, we extend these findings by investigating the therapeutic potential of PolySia-NP to attenuate the alternative complement pathway. First, we show that PolySia-NP binds CFH and enhances affinity to C3b. Next, we demonstrate that PolySia-NP treatment of human serum suppresses alternative pathway hemolytic activity and C3b deposition. Further, we show that treating human macrophages with PolySia-NP is non-toxic and reduces markers of complement activity. Finally, we describe PolySia-NP-treatment-induced decreases in neovascularization and inflammatory response in a laser-induced CNV mouse model of neovascular AMD. In conclusion, PolySia-NP suppresses alternative pathway complement activity in human serum, human macrophage, and mouse CNV without increasing neovascularization.
摘要：
补体系统的替代途径与年龄相关性黄斑变性（AMD）的病因有关。pegcetacoplan和avacincaptadpegol的补体消耗是FDA批准的AMD地理萎缩治疗方法，虽然有效，有临床观察到的脉络膜新生血管（CNV）转换的风险，视神经炎,和视网膜血管炎,为其他同样有效但更安全的疗法留出空间，包括聚唾液酸(PSA)纳米颗粒(PolySia-NP)激活的补体因子H(CFH)替代途径抑制。我们先前的论文证明PolySia-NP抑制促炎极化和细胞因子释放。这里,我们通过研究PolySia-NP减弱替代补体途径的治疗潜力来扩展这些发现.首先,我们显示PolySia-NP结合CFH并增强对C3b的亲和力。接下来,我们证明，PolySia-NP治疗人血清抑制替代途径溶血活性和C3b沉积。Further,我们表明，用PolySia-NP处理人巨噬细胞是无毒的，并且减少了补体活性的标志物。最后,我们描述了在激光诱导的新生血管性AMDCNV小鼠模型中,PolySia-NP治疗诱导的新生血管形成和炎症反应减少.总之,PolySia-NP抑制人血清中的替代途径补体活性，人巨噬细胞,和小鼠CNV而不增加新血管形成。
