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脊柱软膜下的AAV9递送可实现基因沉默与疾病治疗
作者:小柯机器人 发布时间:2019/12/25 11:17:59

美国加州大学圣地亚哥分校Martin Marsala团队发现,脊柱软膜下的AAV9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。相关论文2019年12月23日在线发表在《自然—医学》杂志上。

研究人员开发了一种软膜下技术,该技术已在成年动物中证明能够成功地将腺相关病毒(AAV)传递到整个颈、胸和腰脊髓以及脑运动中心。在表达家族性肌萎缩性侧索硬化症(ALS)的小鼠发病之前,以颈椎和腰椎水平进行一次注射,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 。疾病发作后的治疗有效地阻止了疾病的发展,并进一步阻止了α-运动神经元的退化。使用新设计的设备,在成年猪或非人灵长类动物中一次注射AAV9可以在整个颈脊髓白质和灰质以及脑运动中心产生均匀的输送。因此,成年动物的脊柱软膜下递送对于整个AAV介导的整个脊髓和脊髓上运动中心的基因递送都是非常有效的。

研究人员表示,病毒递送的shRNA基因沉默代表了一种治疗遗传性神经退行性疾病的潜在方法。

附:英文原文

Title: Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS

Author: Mariana Bravo-Hernandez, Takahiro Tadokoro, Michael R. Navarro, Oleksandr Platoshyn, Yoshiomi Kobayashi, Silvia Marsala, Atsushi Miyanohara, Stefan Juhas, Jana Juhasova, Helena Skalnikova, Zoltan Tomori, Ivo Vanicky, Hana Studenovska, Vladimir Proks, PeiXi Chen, Noe Govea-Perez, Dara Ditsworth, Joseph D. Ciacci, Shang Gao, Wenlian Zhu, Eric T. Ahrens, Shawn P. Driscoll, Thomas D. Glenn, Melissa McAlonis-Downes, Sandrine Da Cruz, Samuel L. Pfaff, Brian K. Kaspar, Don W. Cleveland, Martin Marsala

Issue&Volume: 2019-12-23

Abstract: 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.

DOI: 10.1038/s41591-019-0674-1

Source: https://www.nature.com/articles/s41591-019-0674-1

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex