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Published on: August 10, 2018
Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model
Yuki Saito1, Takanori Yokota, Tasuku Mitani
1Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519.
Abstract:
Many autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with copper/zinc superoxide dismutase (SOD1) mutation may be induced by missense point mutations that result in the production of proteins with toxic properties. Reduction in the encoding of proteins from such mutated genes can therefore be expected to improve the disease phenotype. The duplex of 21-nucleotide RNA, known as small interfering RNA (siRNA), has recently emerged as a powerful gene silencing tool. We made transgenic (Tg) mice with modified siRNA, which had multiple mismatch alternations within the sense strand, to prevent the "shutdown phenomenon" of transgenic siRNA. Consequently, the in vivo knockdown effect of siRNA on SOD1 expression did not diminish over four generations. When we crossed these anti-SOD1 siRNA Tg mice with SOD1G93A Tg mice, a model for ALS, siRNA prevented the development of disease by inhibiting mutant G93A SOD1 production in the central nervous system. Our findings clearly proved the principle that siRNA-mediated gene silencing can stop the development of familial ALS with SOD1 mutation.
Insights
Small interfering RNA (siRNA) gene silencing effectively reduced toxic mutant SOD1 protein production in a mouse model of familial amyotrophic lateral sclerosis (ALS). This approach prevented disease development, demonstrating siRNA
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Autosomal dominant diseases, like familial ALS, can stem from missense point mutations causing toxic protein production.
- Reducing the expression of mutated genes is a potential therapeutic strategy for improving disease phenotype.
Purpose of the Study:
- To investigate the efficacy of modified small interfering RNA (siRNA) for in vivo gene silencing of the SOD1 gene in a mouse model of familial ALS.
- To assess the long-term knockdown effect of transgenic siRNA and its impact on disease progression.
Main Methods:
- Generation of transgenic (Tg) mice with modified anti-SOD1 siRNA designed to prevent the shutdown phenomenon.
- Crossing anti-SOD1 siRNA Tg mice with SOD1G93A Tg mice (a model for ALS).
- Monitoring SOD1 expression and disease development in the central nervous system.
Main Results:
- The modified siRNA demonstrated a sustained in vivo knockdown effect on SOD1 expression across four generations.
- Crossing with SOD1G93A Tg mice resulted in the prevention of ALS development.
- Mutant G93A SOD1 production in the central nervous system was inhibited by the siRNA.
Conclusions:
- siRNA-mediated gene silencing is a viable strategy for halting the progression of familial ALS caused by SOD1 mutations.
- This study provides proof of principle for using siRNA therapeutics in neurodegenerative diseases.
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