Department of Neurology, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave, Chicago, IL, 60611, USA.
School of Biological Sciences, Seoul National University, 1, Gwanak-ro, Gwanak-gu, Seoul, 08826, Republic of Korea.
Gene Ther. 2023 Aug;30(7-8):560-574. doi: 10.1038/s41434-023-00383-4. Epub 2023 Feb 24.
Recombinant adeno-associated virus (rAAV)-based gene therapies offer an immense opportunity for rare diseases, such as amyotrophic lateral sclerosis (ALS), which is defined by the loss of the upper and the lower motor neurons. Here, we describe generation, characterization, and utilization of a novel vector system, which enables expression of the active form of hepatocyte growth factor (HGF) under EF-1α promoter with bovine growth hormone (bGH) poly(A) sequence and is effective with intrathecal injections. HGF's role in promoting motor neuron survival had been vastly reported. Therefore, we investigated whether intrathecal delivery of HGF would have an impact on one of the most common pathologies of ALS: the TDP-43 pathology. Increased astrogliosis, microgliosis and progressive upper motor neuron loss are important consequences of ALS in the motor cortex with TDP-43 pathology. We find that cortex can be modulated via intrathecal injection, and that expression of HGF reduces astrogliosis, microgliosis in the motor cortex, and help restore ongoing UMN degeneration. Our findings not only introduce a novel viral vector for the treatment of ALS, but also demonstrate modulation of motor cortex by intrathecal viral delivery, and that HGF treatment is effective in reducing astrogliosis and microgliosis in the motor cortex of ALS with TDP-43 pathology.
基于重组腺相关病毒（rAAV）的基因疗法为罕见病提供了巨大的机会，例如肌萎缩侧索硬化症（ALS），其特征是上运动神经元和下运动神经元的丧失。在这里，我们描述了一种新型载体系统的生成、表征和利用，该系统能够在 EF-1α 启动子下表达活性形式的肝细胞生长因子（HGF），并带有牛生长激素（bGH）聚 A 序列，通过鞘内注射是有效的。HGF 在促进运动神经元存活方面的作用已被广泛报道。因此，我们研究了鞘内注射 HGF 是否会对 ALS 最常见的病理之一：TDP-43 病理产生影响。星形胶质细胞增生、小胶质细胞增生和上运动神经元进行性丧失是具有 TDP-43 病理的运动皮层中 ALS 的重要后果。我们发现通过鞘内注射可以调节皮层，并且表达 HGF 可以减少运动皮层中的星形胶质细胞增生、小胶质细胞增生，并有助于恢复持续的 UMN 退化。我们的发现不仅为 ALS 的治疗引入了一种新型病毒载体，还证明了鞘内病毒传递对运动皮层的调节作用，并且 HGF 治疗在减少具有 TDP-43 病理的 ALS 运动皮层中的星形胶质细胞增生和小胶质细胞增生方面是有效的。
