期刊
SCIENCE ADVANCES
卷 3, 期 12, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aar3952
关键词
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资金
- Ruth L. Kirschstein National Research Service Award (NRSA) [F32GM113446]
- NSF Graduate Research Fellowship
- UC Berkeley Dissertation-Year Fellowship
- Ruth L. Kirschstein NRSA [F32EY023891]
- NIH [R01EY022975]
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord and brain. In particular, autosomal dominant mutations in the superoxide dismutase 1 (SOD1) gene are responsible for similar to 20% of all familial ALS cases. The clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas9) genome editing system holds the potential to treat autosomal dominant disorders by facilitating the introduction of frameshift-induced mutations that can disable mutant gene function. We demonstrate that CRISPR-Cas9 can be harnessed to disrupt mutant SOD1 expression in the G93A-SOD1 mouse model of ALS following in vivo delivery using an adeno-associated virus vector. Genome editing reduced mutant SOD1 protein by >2.5-fold in the lumbar and thoracic spinal cord, resulting in improved motor function and reduced muscle atrophy. Crucially, ALSmice treated by CRISPR-mediated genome editing had similar to 50% more motor neurons at end stage and displayed a similar to 37% delay in disease onset and a similar to 25% increase in survival compared to control animals. Thus, this study illustrates the potential for CRISPR-Cas9 to treat SOD1-linked forms of ALS and other central nervous system disorders caused by autosomal dominant mutations.
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