小柯机器人

美国哥伦比亚大学Livio Pellizzoni团队在研究中取得进展。他们通过腺相关病毒9型血清（AAV9）介导生存运动神经元（SMN）在感觉运动回路中的长期过表达，以此导致毒性功能获得。这一研究成果于2021年4月1日发表在国际顶尖学术期刊《自然-神经科学》杂志上。

他们显示小鼠模型中长期AAV9介导的SMN过表达诱导了与本体感受性突触和神经退行相关的剂量依赖性、迟发性运动功能障碍。从机制上讲，运动神经元细胞质中过表达的SMN聚集会隔离小核核糖核蛋白的成分，导致剪接失调和广泛的转录组异常，并带有神经炎症和先天免疫反应的显著特征。因此，长期的SMN过表达会干扰RNA调节，并通过毒性功能获得机制触发SMA类致病事件。

这些意料之外的、SMN依赖性和神经元特异性的负债在使用AAV9-SMN治疗SMA个体的长期安全性以及通过基因疗法控制蛋白表达的风险方面需要谨慎。

据悉，SMA是由SMN蛋白缺乏引起的。目前批准的SMA治疗旨在恢复SMN，但SMN表达超出生理水平的潜力是AAV9-SMN基因治疗的独特特征。

附：英文原文

Title: Gain of toxic function by long-term AAV9-mediated SMN overexpression in the sensorimotor circuit

Author: Meaghan Van Alstyne, Ivan Tattoli, Nicolas Delestre, Yocelyn Recinos, Eileen Workman, Lamya S. Shihabuddin, Chaolin Zhang, George Z. Mentis, Livio Pellizzoni

Issue&Volume: 2021-04-01

Abstract: The neurodegenerative disease spinal muscular atrophy (SMA) is caused by deficiency in the survival motor neuron (SMN) protein. Currently approved SMA treatments aim to restore SMN, but the potential for SMN expression beyond physiological levels is a unique feature of adeno-associated virus serotype 9 (AAV9)-SMN gene therapy. Here, we show that long-term AAV9-mediated SMN overexpression in mouse models induces dose-dependent, late-onset motor dysfunction associated with loss of proprioceptive synapses and neurodegeneration. Mechanistically, aggregation of overexpressed SMN in the cytoplasm of motor circuit neurons sequesters components of small nuclear ribonucleoproteins, leading to splicing dysregulation and widespread transcriptome abnormalities with prominent signatures of neuroinflammation and the innate immune response. Thus, long-term SMN overexpression interferes with RNA regulation and triggers SMA-like pathogenic events through toxic gain-of-function mechanisms. These unanticipated, SMN-dependent and neuron-specific liabilities warrant caution on the long-term safety of treating individuals with SMA with AAV9-SMN and the risks of uncontrolled protein expression by gene therapy. AAV9-SMN is used to treat SMA. This study shows that AAV9-mediated SMN overexpression in mice causes late-onset motor dysfunction and synaptic and neuronal loss through protein aggregation, suggesting caution on the long-term safety of SMN gene therapy.

DOI: 10.1038/s41593-021-00827-3

Source: https://www.nature.com/articles/s41593-021-00827-3

Nature Neuroscience：《自然—神经科学》，创刊于1998年。隶属于施普林格·自然出版集团，最新IF：28.771
官方网址：https://www.nature.com/neuro/
投稿链接：https://mts-nn.nature.com/cgi-bin/main.plex