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Category CDBセミナー
Date and Time 2016-03-24 16:00 - 17:00
Venue Seminar Room A7F
Speaker Mariko Taniguchi-Ikeda
Affiliation Department of Pediatrics, Kobe University Graduate School of Medicine
Title Antisense therapy for Fukuyama type congenital muscular dystrophy
Poster click here to download(PDF)
Host Keiko Muguruma
Abstract Fukuyama type congenital muscular dystrophy (FCMD) is a second common, severe childhood muscular dystrophy in Japan. All patients have ancestral insertion of a SINE-VNTR-Alu retrotransposal element (SVA) into a causative gene fukutin. We show that aberrant mRNA splicing, induced by SVA exon-trapping caused FCMD. Introduction of three cocktailed antisense oligonucleotides (AONs) targeting around these splice sites prevented pathogenic splicing in FCMD patient cells and model mice, and normalized protein production and functions of Fukutin as well as /O/-glycosylation of α-dystroglycan. Here we show the results of an optimization of the best, single AON for clinical trial. We re-designed AONs precisely around the splice sites and assessed the efficacy for exon trap inhibition of these AONs in FCMD patient cells and model mice. By testing on normal Fukutin production and functional analysis, we finally selected one best candidate AON termed AON-F. Then we also performed /in silico/ analysis if AON-F has off-target or on-target effect on other sites in human genome. We also succeeded in improvement on production efficacy for AON-F. We show the promise of splicing modulation therapy as the first radical clinical treatment for FCMD in the near future.

Taniguchi-Ikeda M, Kobayashi K, Kanagawa M, Yu C, Mori K, Oda T, Kuga A, Kurahashi H, Akman H O, DiMauro S, Kaji R, Yokota T, Takeda S, Toda T. Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy. Nature,478, 127-131.2011.

Kanagawa M, Nishimoto A, Chiyonobu T, Takeda S, Miyagoe-Suzuki Y, Wang F, Fujikake N, Taniguchi M, Lu Z, Tachikawa M, Nagai Y, Tashiro F, Miyazaki J, Tajima Y, Takeda S, Endo T, Kobayashi K, CampbellKP, Toda T. Residual laminin-binding activity and enhanced dystroglycan glycosylation by LARGE in novel model mice to dystroglycanopathy. Hum. Mol. Genet.18,621-631.2009.

Taniguchi M, Kurahashi H, Noguchi S, Sese J, Okinaga T, Tsukahara T, Guicheney P, Ozono K, Nishino I, Morishita S, Toda T. Expression profiling of muscles from Fukuyama-type congenital muscular dystrophy and laminin-alpha2 deficient congenital muscular dystrophy; is congenital muscular dystrophy a primary fibrotic disease? Biochem. Biophys. Res. Commmun.342, 489-502.2006.

Taniguchi M, Kurahashi H, Noguchi S, Fukudome T, Okinaga T, Tsukahara T, Tajima Y, Ozono K, Nishino I, Nonaka I, Toda T. Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in α-dystroglycanopathies. Hum.Mol. Genet.15, 1279-1289.2006.
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