Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial.

IF 4.1 2区医学 Q1 CLINICAL NEUROLOGY Current Opinion in Neurology Pub Date : 2023-12-01 Epub Date: 2023-09-19 DOI:10.1097/WCO.0000000000001205

Elisa M Howard, Stephen M Strittmatter

{"title":"Development of neural repair therapy for chronic spinal cord trauma: soluble Nogo receptor decoy from discovery to clinical trial.","authors":"Elisa M Howard, Stephen M Strittmatter","doi":"10.1097/WCO.0000000000001205","DOIUrl":null,"url":null,"abstract":"Purpose of review: After traumatic spinal cord injury (SCI), neurological deficits persist due to the disconnection of surviving neurons. While repair of connectivity may restore function, no medical therapy exists today.This review traces the development of the neural repair-based therapeutic AXER-204 from animal studies to the recent clinical trial for chronic cervical SCI.Recent findings: Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system (CNS). Rodent and nonhuman primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc or AXER-204 promotes neural repair and functional recovery in transection and contusion SCI. Recently, this biological agent completed a first-in-human and randomized clinical trial for chronic cervical SCI. The intervention was safe and well tolerated. Across all participants, upper extremity strength did not improve with treatment. However, posthoc and biomarker analyses suggest that AXER-204 may benefit treatment-naïve patients with incomplete SCI in the chronic stage.Summary: NgR1 signaling restricts neurological recovery in animal studies of CNS injury. The recent clinical trial of AXER-204 provides encouraging signals supporting future focused trials of this neural repair therapeutic. Further, AXER-204 studies provide a roadmap for the development of additional and synergistic therapies for chronic SCI.","PeriodicalId":11059,"journal":{"name":"Current Opinion in Neurology","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841037/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Current Opinion in Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/WCO.0000000000001205","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/9/19 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Purpose of review: After traumatic spinal cord injury (SCI), neurological deficits persist due to the disconnection of surviving neurons. While repair of connectivity may restore function, no medical therapy exists today.This review traces the development of the neural repair-based therapeutic AXER-204 from animal studies to the recent clinical trial for chronic cervical SCI.

Recent findings: Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system (CNS). Rodent and nonhuman primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc or AXER-204 promotes neural repair and functional recovery in transection and contusion SCI. Recently, this biological agent completed a first-in-human and randomized clinical trial for chronic cervical SCI. The intervention was safe and well tolerated. Across all participants, upper extremity strength did not improve with treatment. However, posthoc and biomarker analyses suggest that AXER-204 may benefit treatment-naïve patients with incomplete SCI in the chronic stage.

Summary: NgR1 signaling restricts neurological recovery in animal studies of CNS injury. The recent clinical trial of AXER-204 provides encouraging signals supporting future focused trials of this neural repair therapeutic. Further, AXER-204 studies provide a roadmap for the development of additional and synergistic therapies for chronic SCI.

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

慢性脊髓损伤神经修复疗法的发展：从发现到临床试验的可溶性nogo受体诱饵。

综述目的：外伤性脊髓损伤（SCI）后，由于存活神经元的断开，神经系统缺陷持续存在。虽然修复连接可以恢复功能，但目前还没有药物治疗。这篇综述追溯了基于神经修复的治疗AXER-204的发展，从动物研究到最近的慢性颈脊髓损伤临床试验。最近的发现：分子研究揭示了Nogo-66受体1（NgR1，RTN4R）通路抑制成年哺乳动物中枢神经系统（CNS）的轴突再生、发芽和可塑性。啮齿动物和非人灵长类动物的研究表明，可溶性受体诱饵NgR（310）ecto-Fc或AXER-204促进横断和挫伤性SCI的神经修复和功能恢复。最近，这种生物制剂完成了一项针对慢性颈椎SCI的首次人体随机临床试验。干预措施安全且耐受性良好。在所有参与者中，上肢力量没有随着治疗而改善。然而，术后和生物标志物分析表明，AXER-204可能有利于治疗慢性期不完全性SCI的幼稚患者。总结：在中枢神经系统损伤的动物研究中，NgR1信号限制神经恢复。AXER-204最近的临床试验提供了令人鼓舞的信号，支持这种神经修复疗法的未来重点试验。此外，AXER-204研究为开发慢性SCI的额外和协同疗法提供了路线图。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

来源期刊

Current Opinion in Neurology 医学-临床神经学

CiteScore

8.60

自引率

0.00%

发文量

174

审稿时长

6-12 weeks

期刊介绍： Current Opinion in Neurology is a highly regarded journal offering insightful editorials and on-the-mark invited reviews; covering key subjects such as cerebrovascular disease, developmental disorders, neuroimaging and demyelinating diseases. Published bimonthly, each issue of Current Opinion in Neurology introduces world renowned guest editors and internationally recognized academics within the neurology field, delivering a widespread selection of expert assessments on the latest developments from the most recent literature.

期刊最新文献

Advances in myopathy research: promising developments and challenges. Neuroinflammation in amyotrophic lateral sclerosis: pathogenic insights and therapeutic implications. Recent insights into haematology and peripheral nerve disease. Obesity-related neuropathy: the new epidemic. Gene therapies for CMT neuropathies: from the bench to the clinic.