Gene silencing with virally delivered shRNA represents a promising approach for treatment of inherited neurodegenerative disorders. In the present study we develop a subpial technique, which we show in adult animals successfully delivers adeno-associated virus (AAV) throughout the cervical, thoracic and lumbar spinal cord, as well as brain motor centers. One-time injection at cervical and lumbar levels just before disease onset in mice expressing a familial amyotrophic lateral sclerosis (ALS)-causing mutant SOD1 produces long-term suppression of motoneuron disease, including near-complete preservation of spinal α-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further α-motoneuron degeneration. A single subpial AAV9 injection in adult pigs or non-human primates using a newly designed device produces homogeneous delivery throughout the cervical spinal cord white and gray matter and brain motor centers. Thus, spinal subpial delivery in adult animals is highly effective for AAV-mediated gene delivery throughout the spinal cord and supraspinal motor centers.

中文翻译：

---

AAV9 的脊髓软膜下递送可实现广泛的基因沉默并阻止 ALS 中的运动神经元变性。

用病毒传递的 shRNA 进行基因沉默代表了一种治疗遗传性神经退行性疾病的有前途的方法。在本研究中，我们开发了一种软膜下技术，我们在成年动物中展示了该技术成功地将腺相关病毒 (AAV) 传递到整个颈椎、胸椎和腰椎脊髓，以及大脑运动中心。在表达家族性肌萎缩侧索硬化 (ALS) 突变 SOD1 的小鼠发病前，在颈椎和腰椎水平注射一次，可长期抑制运动神经元疾病，包括几乎完全保留脊髓 α-运动神经元和肌肉神经支配. 疾病发作后的治疗有效地阻止了疾病的进展和进一步的 α-运动神经元变性。使用新设计的装置在成年猪或非人类灵长类动物中单次注射 AAV9，可在整个颈脊髓白质和灰质以及脑运动中心产生均匀的递送。因此，成年动物的脊髓软膜下递送对于整个脊髓和脊髓上运动中心的 AAV 介导的基因递送非常有效。