腺相关病毒（AAV）可部分纠正小鼠的运动功能障碍以及与肌萎缩侧索硬化症/额颞叶痴呆（ALS/FTLD）相关的病理变化。
AAV- partially corrects motor deficits and ALS/FTLD-related pathology in mice.
作者信息
Feng Tuancheng, Minevich Gregory, Liu Pengan, Qin Henry Xin, Wozniak Glenn, Pham Jenny, Pham Khanh, Korgaonkar Akshata, Kurnellas Michael, Defranoux Nadine A, Long Hua, Mitra Ananya, Hu Fenghua
机构信息
Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
Alector Inc, South San Francisco, CA 94080, USA.
出版信息
iScience. 2023 Jun 28;26(7):107247. doi: 10.1016/j.isci.2023.107247. eCollection 2023 Jul 21.
Loss of function of progranulin (PGRN), encoded by the () gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show that intracerebral ventricle injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in mice. Widespread expression of PGRN is detected in both the brain and spinal cord for both AAV subtypes. However, AAV9 but not AAV1-mediated expression of PGRN results in high levels of PGRN in the serum. Together, these data support using the mouse strain as a robust mouse model to determine the efficacy of PGRN-elevating therapeutics.
由（）基因编码的前颗粒蛋白（PGRN）功能丧失与多种神经退行性疾病有关。目前有几种提高PGRN水平的治疗方法正在进行临床试验。然而，由于小鼠的表型较轻，很难在小鼠模型中测试提高PGRN药物的疗效。最近，研究表明，同时缺乏PGRN和跨膜蛋白106B（TMEM106B）的小鼠会出现严重的运动缺陷和病理变化。在此，我们表明，向脑室内注射表达PGRN的腺相关病毒1/9（AAV1/9）可部分挽救小鼠的运动缺陷、神经元丢失、神经胶质激活和溶酶体异常。两种AAV亚型在脑和脊髓中均检测到PGRN的广泛表达。然而，AAV9介导而非AAV1介导的PGRN表达会导致血清中PGRN水平升高。总之，这些数据支持使用小鼠品系作为一个强大的小鼠模型来确定提高PGRN治疗方法的疗效。
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