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.
摘要:
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性转录因子。在成人中,慢病毒(LV)介导的Gsx1表达促进外侧半切脊髓损伤(SCI)小鼠模型中的神经再生和功能性运动恢复。由于宿主DNA的插入突变,LV递送方法在临床上是不安全的。此外,最常见的SCI临床病例是挫伤/压迫.在这项研究中,我们确定腺相关病毒血清型6(AAV6)优先感染受损脊髓中的神经干/祖细胞(NSPCs).使用大鼠模型的挫伤SCI,我们证明AAV6介导的Gsx1表达促进神经发生,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性/抑制性神经元平衡和5-羟色胺能神经元活动,并促进运动功能恢复。我们的发现支持AAV6优先靶向NSPCs进行基因传递,并证实了Gsx1在临床相关大鼠模型中的挫伤SCI的功效。