期刊
NATURE MEDICINE
卷 26, 期 1, 页码 118-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-019-0674-1
关键词
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资金
- National Sustainability Program I, of the Czech Ministry of Education, Youth and Sports [LO1609]
- RVO [67985904]
- Slovak Research and Development Agency [APVV-15-0665, APVV 14-0847]
- Scientific Grant Agency of the Ministry of Education, Science, Research and Sport of the Slovak Republic
- Slovak Academy of Sciences [VEGA 2/0086/16]
- Czech Science Foundation [18-04393S]
- NIH [R01-EB024015]
- California Institute for Regenerative Medicine [LA1-C12-06919]
- ALS Association
- Sanford Porcine Center
Injection of AAV-shRNA below the pial surface of the spinal cord prevents onset or ameliorates progression in a mouse model of ALS, and achieves widespread delivery to the spinal cord and brain motor centers in adult pigs and non-human primates. 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 alpha-motoneurons and muscle innervation. Treatment after disease onset potently blocks progression of disease and further alpha-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.
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