期刊
MOLECULAR THERAPY
卷 25, 期 9, 页码 2038-2052出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2017.05.017
关键词
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资金
- Association Francaise contre les Myopathies (AFM)
- University Pierre et Marie Curie (UPMC)
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Centre National de la Recherche Scientifique (CNRS)
- Association Institut de Myologie (AIM)
- Otto per Mille Waldensian Church
- Association pour la Recherche sur la Sclerose Laterale Amyotrophique (ARSLA)
- NIHR GOSH Biomedical Research Centre
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD). Skipping of hSOD1 exon 2 led to the generation of a premature termination codon, inducing production of a deleted transcript that was subsequently degraded by the activation of nonsense mediated decay. Combined intravenous and intracerebroventricular delivery of AAV10-U7-hSOD increased the survival of SOD1G93A mice injected either at birth or at 50 days of age (by 92% and 58%, respectively) and prevented weight loss and the decline of neuromuscular function. This study reports the effectiveness of an exon-skipping approach in SOD1-ALS mice, supporting the translation of this technology to the treatment of this as yet incurable disease.
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