Abstract:
Due to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases. We previously reported the activation of Fas-mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H, and demonstrated the protective effect of genetic Fas inhibition. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation, rate of PR cell death, retinal function, and the activation of immune cells in the retina were evaluated. In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) PRs, decreased caspase 8 activity, enhanced photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. Treatment with ONL1204 also reduced immune cell activation in the retinas of both rd10 and P23H mice. The protective effect of pharmacologic inhibition of Fas by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential therapeutic approach to preserve the retina in patients with IRD, regardless of the genetic underpinning.
摘要:
由于大量的基因和突变导致遗传性视网膜变性(IRD),这些患者的治疗选择很少。对于以不依赖于突变的方式靶向共有的病理生理途径的治疗方法存在大量未满足的需求。Fas受体是多种眼部疾病中视网膜细胞逝世亡和炎症的主要激活剂和调理剂。我们先前报道了两种不同IRD小鼠模型中Fas介导的光感受器(PR)细胞死亡的激活,rd10和P23H,并证明了基因Fas抑制的保护作用。这项研究的目的是通过玻璃体内注射Fas受体的小肽抑制剂来检查这两种模型中Fas的药理抑制作用,ONL1204.在P14时对rd10小鼠的一只眼睛给予ONL1204的单次玻璃体内注射。给P23H小鼠两次玻璃体内注射ONL1204,一次在P14和2个月大时再次。同伴的眼睛只被车辆注射。Fas激活,PR细胞死亡率,视网膜功能,并评估了视网膜中免疫细胞的激活。在rd10和P23H小鼠中,ONL1204治疗导致TUNEL(+)PR数量减少,caspase8活性降低,增强感光细胞计数,与车辆处理的同伴眼睛相比,视觉功能得到了改善。用ONL1204治疗还降低了rd10和P23H小鼠视网膜中的免疫细胞活化。在两种不同的视网膜变性小鼠模型中,ONL1204对Fas的药理抑制作用表明,靶向细胞死亡和炎症的这种常见病理生理机制代表了一种潜在的治疗方法,可以保护IRD患者的视网膜。不管基因支撑。