Pleiotropic activity of systemically delivered angiogenin in the SOD1G93A mouse model
Pleiotropic activity of systemically delivered angiogenin in the SOD1G93A mouse model
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DOI：
10.1016/j.neuropharm.2018.02.022
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发表时间：
2018-05-01
影响因子：
4.7
通讯作者：
Prehn, Jochen H. M.
中科院分区：
文献类型：
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作者：
Crivello, Martin;O'Riordan, Saidhbhe L.;Prehn, Jochen H. M.
在家族性和散发性 ALS 患者中已发现血管生成素 (ANG) 基因的功能丧失突变。我们小组之前的工作在体外鉴定了人 ANG (huANG) 可以保护运动神经元，并提供了概念验证，即症状出现后每日腹腔 (i.p.) 注射 huANG 可延长 SOD1(G93A) 小鼠的寿命并延缓疾病进展。 huANG 的作用机制仍不太清楚。在这里，我们实施了临床前体内设计来验证我们之前的结果，提供全身给药后的药代动力学和蛋白质分布数据，并探索 huANG 在体内潜在的多效性活性。根据 2010 年欧洲 ALS/MND 小组指南，SOD1(G93A) 小鼠 (n = 45) 和非转基因对照小鼠 (n = 31) 进行性别年龄和窝匹配，并从 90 天起用 huANG（1 微克，腹膜内注射，每周 3 次）或媒介物治疗。通过旋转棒对 SOD1(G93A) 小鼠进行评估，huANG 治疗可提高存活率并延迟运动功能障碍。腹腔注射后 2 小时和 24 小时可检测到 huANG 血清水平升高。对转基因和非转基因小鼠进行同等注射。外源性 huANG 定位于脊髓星形胶质细胞，支持神经胶质介导的旁分泌作用机制；还观察到内皮细胞的摄取。从90日龄至115日龄施用1μg huANG或媒介物用于组织学分析。载体处理的 SOD1(G93A) 小鼠表现出每个腹角区域的运动神经元数量和血管长度减少，而 huANG 治疗则改善了血管网络的维持和运动神经元的存活。我们的数据表明，huANG 代表了一类新型多效性 ALS 治疗药物，作用于脊髓血管系统和神经胶质细胞，延缓运动神经元变性和疾病进展。 (C) 2018 Elsevier Ltd. 保留所有权利。
Loss-of-function mutations in the angiogenin (ANG) gene have been identified in familial and sporadic ALS patients. Previous work from our group identified human ANG (huANG) to protect motoneurons in vitro, and provided proof-of-concept that daily intraperitoneal (i.p.) huANG injections post-symptom onset increased lifespan and delayed disease progression in SOD1(G93A) mice. huANG's mechanism of action remains less well understood. Here, we implemented a preclinical in vivo design to validate our previous results, provide pharmacokinetic and protein distribution data after systemic administration, and explore potential pleiotropic activities of huANG in vivo. SOD1(G93A) mice (n = 45) and non-transgenic controls (n = 31) were sex- age- and litter-matched according to the 2010 European ALS/MND group guidelines, and treated with huANG (1 mu g, i.p., 3 times/week) or vehicle from 90 days on. huANG treatment increased survival and delayed motor dysfunction as assessed by rotarod in SOD1(G93A) mice. Increased huANG serum levels were detectable 2 and 24 h after i.p. injection equally in transgenic and non-transgenic mice. Exogenous huANG localized to spinal cord astrocytes, supporting a glia-mediated, paracrine mechanism of action; uptake into endothelial cells was also observed. 1 mu g huANG or vehicle were administered from 90 to 115 days of age for histological analysis. Vehicle-treated SOD1(G93A) mice showed decreased motoneuron numbers and vascular length per ventral horn area, while huANG treatment resulted in improved vascular network maintenance and motoneuron survival. Our data suggest huANG represents a new class of pleiotropic ALS therapeutic that acts on the spinal cord vasculature and glia to delay motoneuron degeneration and disease progression. (C) 2018 Elsevier Ltd. All rights reserved.