title: Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model.
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.
authors.affiliation: Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Saito
authors.forename: Takanori
authors.initials: T
authors.lastname: Yokota
authors.forename: Tasuku
authors.initials: T
authors.lastname: Mitani
authors.forename: Kaoru
authors.initials: K
authors.lastname: Ito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Anzai
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyagishi
authors.forename: Kazunari
authors.initials: K
authors.lastname: Taira
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Mizusawa
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000628:therapy*; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020868:Gene Silencing; D005822:Genetic Vectors; D016678:Genome; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D017354:Point Mutation; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics*; D013997:Time Factors; D019076:Transgenes
chemical_list: D034741:RNA, Small Interfering; D013482:Superoxide Dismutase