Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
Gene therapy targeting SARM1 blocks pathological axon degeneration in mice
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DOI：
10.1084/jem.20181040
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发表时间：
2019-02-01
影响因子：
15.3
通讯作者：
Milbrandt, Jeffrey
中科院分区：
文献类型：
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作者：
Geisler, Stefanie;Huang, Shay X.;Milbrandt, Jeffrey
神经损伤、化疗和几种神经系统疾病后的轴突变性（AxD）是由SARM 1（一种损伤激活的NAD酶）驱动的主动过程。SARM 1基因敲除小鼠的轴突在横断后和神经系统疾病模型中表现出极大的延迟AxD，这表明抑制SARM 1是减少病理性AxD的一种有希望的策略。不幸的是，目前还没有针对SARM 1的药物。因此，我们开发了SARM 1显性阴性，在轴突切断和神经病变的细胞模型中有效地阻断AxD。为了评估体内疗效，我们使用腺相关病毒介导的最有效的SARM 1显性阴性表达和神经横断作为严重AxD的模型。虽然媒介物处理的小鼠的轴突迅速退化，但表达SARM 1显性阴性的小鼠的轴突在横切后可以保持完整>10天，与在SARM 1缺失小鼠中观察到的保护相似。因此，我们开发了一种新的体内基因治疗药物，通过抑制SARM 1来阻断病理性轴突变性，这种方法可以在临床上应用于治疗以轴突丢失为特征的多种神经退行性疾病。
Axonal degeneration (AxD) following nerve injury, chemotherapy, and in several neurological disorders is an active process driven by SARM1, an injury-activated NADase. Axons of SARM1-null mice exhibit greatly delayed AxD after transection and in models of neurological disease, suggesting that inhibiting SARM1 is a promising strategy to reduce pathological AxD. Unfortunately, no drugs exist to target SARM1. We, therefore, developed SARM1 dominant-negatives that potently block AxD in cellular models of axotomy and neuropathy. To assess efficacy in vivo, we used adeno-associated virus-mediated expression of the most potent SARM1 dominant-negative and nerve transection as a model of severe AxD. While axons of vehicle-treated mice degenerate rapidly, axons of mice expressing SARM1 dominant-negative can remain intact for >10 d after transection, similar to the protection observed in SARM1-null mice. We thus developed a novel in vivo gene therapeutic to block pathological axon degeneration by inhibiting SARM1, an approach that may be applied clinically to treat manifold neurodegenerative diseases characterized by axon loss.