AAV6 mediated Gsx1 expression in neural stem progenitor cells promotes neurogenesis and restores locomotor function after contusion spinal cord injury

IF 5.6 2区医学 Q1 CLINICAL NEUROLOGY Neurotherapeutics Pub Date : 2024-07-01 DOI:10.1016/j.neurot.2024.e00362

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Abstract

Genomic screened homeobox 1 (Gsx1 or Gsh1) is a neurogenic transcription factor required for the generation of excitatory and inhibitory interneurons during spinal cord development. In the adult, lentivirus (LV) mediated Gsx1 expression promotes neural regeneration and functional locomotor recovery in a mouse model of lateral hemisection spinal cord injury (SCI). The LV delivery method is clinically unsafe due to insertional mutations to the host DNA. In addition, the most common clinical case of SCI is contusion/compression. In this study, we identify that adeno-associated virus serotype 6 (AAV6) preferentially infects neural stem/progenitor cells (NSPCs) in the injured spinal cord. Using a rat model of contusion SCI, we demonstrate that AAV6 mediated Gsx1 expression promotes neurogenesis, increases the number of neuroblasts/immature neurons, restores excitatory/inhibitory neuron balance and serotonergic neuronal activity through the lesion core, and promotes locomotor functional recovery. Our findings support that AAV6 preferentially targets NSPCs for gene delivery and confirmed Gsx1 efficacy in clinically relevant rat model of contusion SCI.

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AAV6 介导的 Gsx1 在神经干祖细胞中的表达可促进神经发生并恢复挫伤性脊髓损伤后的运动功能。

基因组筛选同源框 1（Gsx1 或 Gsh1）是脊髓发育过程中产生兴奋性和抑制性中间神经元所需的神经源性转录因子。在成年脊髓损伤（SCI）小鼠模型中，慢病毒（LV）介导的 Gsx1 表达可促进神经再生和运动功能恢复。由于宿主 DNA 的插入突变，LV 传播方法在临床上并不安全。此外，SCI 最常见的临床病例是挫伤/压迫。在这项研究中，我们发现腺相关病毒血清型6（AAV6）会优先感染损伤脊髓中的神经干/祖细胞（NSPC）。我们利用大鼠挫伤性脊髓损伤模型证明，AAV6介导的Gsx1表达可促进神经发生，增加神经母细胞/未成熟神经元的数量，通过病变核心恢复兴奋/抑制神经元平衡和5-羟色胺能神经元活性，并促进运动功能恢复。我们的研究结果支持 AAV6 优先靶向 NSPCs 进行基因递送，并证实了 Gsx1 在临床相关的挫伤性 SCI 大鼠模型中的疗效。

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来源期刊

Neurotherapeutics 医学-神经科学

CiteScore

11.00

自引率

3.50%

发文量

154

审稿时长

6-12 weeks

期刊介绍： Neurotherapeutics® is the journal of the American Society for Experimental Neurotherapeutics (ASENT). Each issue provides critical reviews of an important topic relating to the treatment of neurological disorders written by international authorities. The Journal also publishes original research articles in translational neuroscience including descriptions of cutting edge therapies that cross disciplinary lines and represent important contributions to neurotherapeutics for medical practitioners and other researchers in the field. Neurotherapeutics ® delivers a multidisciplinary perspective on the frontiers of translational neuroscience, provides perspectives on current research and practice, and covers social and ethical as well as scientific issues.