Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury
Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury
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DOI：
10.1093/brain/awaa116
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发表时间：
2020-06-01
期刊：
影响因子：
14.5
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
--
作者：
Wang, Xingxing;Zhou, Tianna;Strittmatter, Stephen M.
在脊髓损伤等中枢神经系统创伤后，存活的神经元件长出轴突、重组神经网络和支持功能恢复的能力受到严重限制，导致慢性神经功能缺损。神经恢复的局限性之一是髓磷脂相关抑制剂作为神经元Nogo受体1 （NgR1）的配体。一种可溶性诱饵（NgR1-Fc,AXER-204）阻断这些配体，并在多种临床前啮齿动物脊髓损伤模型中提供了促进功能恢复的手段。然而，该试剂在非人灵长类动物脊髓损伤中的安全性和有效性及其毒理学特征尚未得到描述。在这里，我们提供的证据表明，食蟹猴和大鼠慢性鞘内和静脉给药NgR1-Fc，每隔一天给药20mg或更大剂量（52.0 mg/kg/天），远高于人类的预期剂量，没有明显的毒性。成年雌性非洲绿猴接受右侧C5/6外侧半切断术，进食时右前肢持续失用，运动时右后肢持续失用。损伤后1个月，动物随机分为载药组（n = 6）和经鞘内腰椎导管和渗透性微型泵给予0.10-0.17 mg/kg/天NgR1-Fc组（n = 8），持续4个月。由于导管的手术并发症，一只动物被从研究中移除，但两组均未发现与治疗相关的不良事件。在损伤后6-7个月，即停止治疗后1-2个月评估动物行为。治疗组自发进食时前肢损伤的使用和运动时后肢损伤的使用均显著增加。损伤后7-12个月收集的组织在病变大小、纤维化瘢痕、胶质增生和神经炎症方面各组间无显著差异。两组损伤下方的5 -羟色胺能肾上腺纤维未见缺损，损伤侧和完好侧的密度相等。左运动皮层生物素-右旋氨基注射追踪到的皮质脊髓轴突在各组中被平等标记，并在损伤的尾侧减少。NgR1-Fc组脑组织损伤水平以下颈髓皮质脊髓轴突密度较载药组显著增加2-3倍。数据显示，NgR1-Fc在健康动物中没有临床前毒理学问题，在脊髓损伤动物中也没有安全性问题。因此，它作为一种潜在的脊髓损伤治疗方法，有证据表明，它可以改善非人灵长类动物脊髓损伤的行为和损伤通路的生长。
After CNS trauma such as spinal cord injury, the ability of surviving neural elements to sprout axons, reorganize neural networks and support recovery of function is severely restricted, contributing to chronic neurological deficits. Among limitations on neural recovery are myelin-associated inhibitors functioning as ligands for neuronal Nogo receptor 1 (NgR1). A soluble decoy (NgR1-Fc,AXER-204) blocks these ligands and provides a means to promote recovery of function in multiple preclinical rodent models of spinal cord injury. However, the safety and efficacy of this reagent in non-human primate spinal cord injury and its toxicological profile have not been described. Here, we provide evidence that chronic intrathecal and intravenous administration of NgR1-Fc to cynomolgus monkey and to rat are without evident toxicity at doses of 20 mg and greater every other day (52.0 mg/kg/day), and far greater than the projected human dose. Adult female African green monkeys underwent right C5/6 lateral hemisection with evidence of persistent disuse of the right forelimb during feeding and right hindlimb during locomotion. At 1 month post-injury, the animals were randomized to treatment with vehicle (n = 6) or 0.10-0.17 mg/kg/day of NgR1-Fc (n = 8) delivered via intrathecal lumbar catheter and osmotic minipump for 4 months. One animal was removed from the study because of surgical complications of the catheter, but no treatment-related adverse events were noted in either group. Animal behaviour was evaluated at 6-7 months post-injury, i.e. 1-2 months after treatment cessation. The use of the impaired forelimb during spontaneous feeding and the impaired hindlimb during locomotion were both significantly greater in the treatment group. Tissue collected at 7-12 months post-injury showed no significant differences in lesion size, fibrotic scar, gliosis or neuroinflammation between groups. Serotoninergic raphespinal fibres below the lesion showed no deficit, with equal density on the lesioned and intact side below the level of the injury in both groups. Corticospinal axons traced from biotin-dextran-amine injections in the left motor cortex were equally labelled across groups and reduced caudal to the injury. The NgR1-Fc group tissue exhibited a significant 2-3-fold increased corticospinal axon density in the cervical cord below the level of the injury relative to the vehicle group. The data show that NgR1-Fc does not have preclinical toxicological issues in healthy animals or safety concerns in spinal cord injury animals. Thus, it presents as a potential therapeutic for spinal cord injury with evidence for behavioural improvement and growth of injured pathways in nonhuman primate spinal cord injury.