Pre-clinical evaluation of an sLex-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke
Pre-clinical evaluation of an sLex-glycosylated complement inhibitory protein in a non-human primate model of reperfused stroke
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DOI：
10.1111/j.1600-0684.2007.00213.x
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发表时间：
2007-12-01
影响因子：
0.7
通讯作者：
Connolly, E. Sander, Jr.
中科院分区：
文献类型：
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作者：
Ducruet, Andrew F.;Mocco, J.;Connolly, E. Sander, Jr.
背景：可溶性补体受体-1(SCR1)是一种有效的补体抑制剂，在小鼠卒中模型中具有神经保护作用。通过sCR1的SLE(X)糖基化实现了额外的神经保护益处。为了将sCR1-SLE(X)转化为临床试验，我们在灵长类中风模型中对该药物进行了评估。在第3天评估每搏量，并每天进行神经学检查。分别于缺血后30分钟、2、6、12小时、3天和10天测定补体活性(CH50)。在初步队列中(n=3)，接受治疗的动物的脑梗塞体积更大。两组间神经功能评分无差异。SCR1sLe(X)处理组的CH50水平显著降低。在用sCR1-SLE(X)治疗的动物中也观察到了降压反应。结论在sCR1-SLE(X)的进一步临床发展之前，还需要进一步的工作来解释在灵长类动物中观察到的降压反应。
Background Soluble complement receptor-1 (sCR1), a potent complement inhibitor, confers neuroprotection in a murine stroke model. Additional neuroprotective benefit is achieved by sLe(x)-glycosylation of sCR1. In an effort to translate sCR1-sLe(x) to clinical trials, we evaluated this agent in a primate stroke model.Methods Adult male baboons randomly received either sCR1-sLe(x) or vehicle. Stroke volume was assessed on day 3, and neurological examinations were conducted daily. Complement activity (CH50) was measured at 30 minute, 2, 6, 12 hour, 3, and 10 days post-ischemia.Results The experiment was terminated prematurely following an interim analysis. In a preliminary cohort (n = 3 per arm), infarct volume was greater in the treated animals. No difference in neurological score was found between groups. CH50 levels were significantly reduced in the sCR1sLe(x)-treated groups. A hypotensive response was also observed in animals treated with sCR1-sLe(x).Conclusions Further work is necessary to explain the hypotensive response observed in primates prior to further clinical development of sCR1-sLe(x).