New Treatment Strategy for SMA: In tron-retention of the SMN2 gene
| Project/Area Number |
17K10077
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kobe Gakuin University (2018-2019)
Kobe University (2017) |
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Principal Investigator |
Nishio Hisahide 神戸学院大学, 総合リハビリテーション学部, 教授 (80189258)
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| Co-Investigator(Kenkyū-buntansha) |
篠原 正和 神戸大学, 医学研究科, 准教授 (80437483)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 脊髄性筋萎縮症 / SMN１遺伝子 / SMN２遺伝子 / イントロン・リテンション / スプライス部位 / アンチセンスオリゴヌクレオチド / ヌシネルセン / オフターゲット効果 / SMN1遺伝子 / SMN2遺伝子 / スプライシング / 潜在性エクソン / 新規治療法 |
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| Outline of Final Research Achievements |
Spinal muscular atrophy (SMA) is a motor neuron disease caused by SMN1 gene abnormality. We planned to develop a new treatment strategy for SMA in this project. To produce a higher amount of full-length SMN2 protein in SMA fibroblasts, we designed experiments in which SMN2 intron 7-retention should be induced by antisense oligonucleotide agents (AO). However, when SMA fibroblasts were transfected with AOs targeting the splice sites of SMNN2 intron 7, unexpected results were obtained; retention of intron 7 was hardly introduced, but exon 7 was rather incorporated into SMN2 mRNA. Our study revealed that AO, which targeted the splice sites of intron 7, might induce SMN2 exon 7 inclusion, suggesting that our AOs might have splicing-enhancing function. We also did experiments with Nusinesrsen-like AO (Nusi). High dose of Nusi produced a new transcript with a cryptic exon in SMN2 intron 6, suggesting the possibility of Nusinersen's off-target effect.
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| Academic Significance and Societal Importance of the Research Achievements |
（学術的意義）SMN2遺伝子エクソン7において、スプライス部位を標的としたアンチセンスオリゴヌクレオチド（AO）がスプライシングを阻止しないで、かえってスプライシング増強機能を示したことは、スプライシング装置が遺伝子によって異なることを示している。
（社会的意義）ヌシネルセンは、SMA治療薬として、2016年米国で、翌年わが国で薬事承認を受けた。わが国では、400人を超えるSMA患者が本薬剤で治療を受けている。本薬剤のオフターゲット効果は報告されていないが、今回の実験結果はオフターゲット効果の存在を示唆している。ヌシネルセンの投与に際しては、今後も慎重な観察が必要である。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Intron-retained transcripts of the spinal muscular atrophy genes, SMN1 and SMN2.2018
Author(s)
Harahap NIF, Niba ETE, Ar Rochmah M, Wijaya YOS, Saito T, Saito K, Awano H, Morioka I, Iijima K, Lai PS, Matsuo M, Nishio H, Shinohara M.
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Journal Title
Brain & Devwlopment
Volume: 40
Issue: 8
Pages: 670-677
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Genetic screening of spinal muscular atrophy using a real-time modified COP-PCR technique with dried blood-spot DNA2017
Author(s)
Ar Rochmah M, Harahap NIF, Niba ETE, Nakanishi K, Awano H, Morioka I, Iijima K, Saito T, Saito K, Lai PS, Takeshima Y, Takeuchi A, Bouike Y, Okamoto M, Nishio H, Shinohara M
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Journal Title
Brain Dev.
Volume: 39(9)
Issue: 9
Pages: 774-782
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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