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Development of Therapy for Spinal Muscular Atrophy Based on the Spliring Modulation Technology

Research Project

Project/Area Number 18591151
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionKobe University

Principal Investigator

NISHIO Hisahide  Kobe University, Graduate School of Medicine, Professor (80189258)

Co-Investigator(Kenkyū-buntansha) TAKESHIMA Yasuhiro  Kobe University, Graduate School of Medicine, Assistant professor (40281141)
LEE Myeong, Jin  Kobe University, Graduate School of Medicine, Assistant professor (20273766)
綾木 仁  神戸大学, 大学院医学系研究科, 助教授 (80222701)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
Keywordsspinal muscular atrophy / the SMN1 gene / the SMN2 gene / thetic exon-specific splicing activator / valproic acid / ヒストン脱アセチル化酵素阻害剤 / 転写効率 / スプライシング効率 / エクソン7 / スプライシング / ペプチド核酸 / 遺伝子変異 / Tudorドメイン
Research Abstract

1. (Background) More than 90% of patients with spinal muscular atrophy (SMA) are homozygous for SMN1 deletion. However, SMN2 is retained in such patients. SMN2 is an almost identical gene to SMN1 and codes the same protein as SMN1 does. The main product of SMN2 is a transcript lacking exon7, producing truncated SMN protein. That is the reason why SMN2 cannot compensate the loss of SMNI in most SMA patients. A single nucleotide change in exon 7, 6C in SMN1 and 6T in SMN2, makes the splicing difference between them. Correction of the exon 7 splicing of SMN2 is now considered as a treatment strategy for SMA.
2. (Synthetic exon-specific splicing activator) Based on the report of Cartegni, et. al., we synthesized a peptide nucleic acid, SMN-PNA (ESSENCE), which may activate splicing of SMN2 exon 7. SMN-PNA had SMN2 exon 7 binding domain and serine-arginine repeat domain. Our study using fibroblast cell line from an SMA patient did not show at all that SMN-PNA corrected the splicing pattern, while in-vitro splicing assay with SMN2EX6-7 plasmid showed some effects on the splicing pattern.
3. (Splicing modulating drug) Valproic acid (VPA) is widely used as an antiepileptic drug. Recently, it has been reported that VPA may increase SMN2 expression and alter its splicing pattern. We tested whether VPA can increase SMN2 gene expression in the fibroblasts from our SMA patients. The effect of VPA (concentration of 0.5-1000 μM) on total transcription level and exon 7-splicing pattern of SMN2 in the fibroblasts was evaluated by quantitative PCR method. VPA did not alter significantly the total transcription level and splicing pattern of SMN2 in this study, suggesting that there are non-responders to VPA treatment.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report

Research Products

(24 results)

All 2008 2007 2006

All Journal Article (17 results) (of which Peer Reviewed: 10 results) Presentation (7 results)

  • [Journal Article] Hypomutability at the Polyadenine Tract in SMN Intron 3 Shows the Invariability of the a-SMN Protein Structure.2008

    • Author(s)
      Gunadi, Sasongko TH, Yusoff S, Lee MJ, Nishioka E, matsuo M, Nishio H.
    • Journal Title

      Ann Hum Genet. 72

      Pages: 288-291

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] SMN2 and NAIP gene dosages in Vietnamese patients with spinal muscular atrophy.2008

    • Author(s)
      Van Khanh TV, Teguh Haryo Sasongko, Dang Diem Hong, Nguyen Thi Hoan, Vu Chi Dung, Myeong Jin Lee, Gunadi, Indra Sari Kusumma Harahap, Yasuhiro Takeshima, Masafumi Matsuo and Hisahide Nishio.
    • Journal Title

      Pediatrics International (in press)

    • NAID

      10025343726

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Hypomutability at the Polyadenine Tract in SMN Intron 3 Shows the Invariability of the a-SMN Protein Structure2008

    • Author(s)
      Gunadi, Sasongko, TH, Yusoff, S, Lee, MJ, Nishioka, E, Matsuo, M, Nishio, H
    • Journal Title

      Ann Hum Genet 72(2)

      Pages: 288-291

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] SMN2 and NAP gene dosages in Vietnamese patients with spinal muscular atrophy2008

    • Author(s)
      Van, Khanh, TV, Teguh, Haryo, Sasongko, Dang, Diem Hong , Nguyen, Thi, Hoan, Vu, Chi, Dung, Myeongn Jin Lee , Gunadi, Indra, Sari, Kusuma, Harahap, Yasuhiro, Takeshima, Masafumi, Matsuo, Hisahide, Nishio
    • Journal Title

      Pediatr Int (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Zilfalil BA. Deletion analyses of SMN1 and NAIP genes in Malaysian spinal muscular atrophy patients.2007

    • Author(s)
      Watihayati MS, Zabidi-Hussin AM, Tang TH, Matsuo M, Nishio H.
    • Journal Title

      Pediatr Int. 49

      Pages: 303-303

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] C117T variant in the SMN1 gene found in the Japanese population.2007

    • Author(s)
      Sadcwa AH, Harada Y, Sasongko TH, Matsuuo M, Nishio H.
    • Journal Title

      Pediatr Int. 254

      Pages: 8-10

    • NAID

      10018837429

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins.2007

    • Author(s)
      Kotani T, Sutomo R, Sasongko TH, Sadewa AH, Gunadi, Minato T, Fujii E, Endo S, Lee MJ, Ayaki H, Harada Y, Matsuo M, Nishio H.
    • Journal Title

      J Neurol. 80

      Pages: 624-630

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Zilfalil B. A. NAIP-Deletion Analysis in Malaysian Patients with Spinal Muscular Atrophy.2007

    • Author(s)
      Watihayati M.S., Zabidi-Hussin A. M. H., Tang T. H., Nishio H.,
    • Journal Title

      Kobe J Med Sci. 53

      Pages: 171-175

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Deletion analyses of SMN1 and NAP genesin Malaysian spinal muscular atrophy patients2007

    • Author(s)
      Watihayati, MS, Zabidi-Hussin, AM, Tang, TH, Matsuo, M, Nishio, H, Zilfalil, BA
    • Journal Title

      Pediatr Int 49(1)

      Pages: 11-4

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] C117T variant in the SMN1 gene found in the Japanese population2007

    • Author(s)
      Sadewa, AH, Harada, Y, Sasongko, TH, Matsuo, M, Nishio, H
    • Journal Title

      Pediatr Int 49(1)

      Pages: 8-10

    • NAID

      10018837429

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins2007

    • Author(s)
      Kotani, T, Sutomo, R, Sasongko, TH, Sadewa, AH, Gunadi, Minato, T,Fujii, E, Endo, S, Lee, MJ, Ayaki, H, Harada, Y, Matsuo, M, Nishio, H
    • Journal Title

      J Neurol 254(5)

      Pages: 624-30

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] NAIP-Deletion Analysis in Malaysian Patients with Spinal Muscular Atrophy2007

    • Author(s)
      Watihayati, M.S., Zabidi-Hussin, A.M.H., Tang, T.H., Nishio, H., Zilfalil, B.A
    • Journal Title

      Kobe J Med Sci 53(4)

      Pages: 171-5

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins.2007

    • Author(s)
      Kotani T, Sutomo R, Sasongko TH, Sadewa AH, Gunadi, Minato T, Fujii E, Endo S, Lee MJ, Ayaki H, Harada Y, Matsuo M, Nishio H.
    • Journal Title

      J Neurol. 254

      Pages: 624-30

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] C117T variant in the SMN1 gene found in the Japanese population.2007

    • Author(s)
      Sadewa AH, Harada Y, Sasongko TH, Matsuo M, Nishio H.
    • Journal Title

      Pediatr Int. 49

      Pages: 8-10

    • NAID

      10018837429

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Deletion analyses of SMN1 and NAIP genes in Malaysian spinal muscular atrophy patients.2007

    • Author(s)
      Watihayati MS, Zabidi-Hussin AM, Tang TH, Matsuo M, Nishio H, Zilfalil BA.
    • Journal Title

      Pediatr Int. 49

      Pages: 11-4

    • NAID

      10018837439

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cadmium restores in vitro splicing activity inhibited by zinc-depletion.2006

    • Author(s)
      Lee MJ, Ayaki H, Goji J, Kitamura K, Nishio
    • Journal Title

      Arch Toxicol. 80

      Pages: 638-643

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Cadmium restores in vitro splicing activity inhibited by zinc-depletion2006

    • Author(s)
      Lee, MJ, Ayaki, H, Goji, J, Kitamura, K, Nishio, H
    • Journal Title

      Arch Toxicol 80(10)

      Pages: 638-43

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Genetics of Spinal Muscular Atrophy2008

    • Author(s)
      Nishio, H
    • Organizer
      The Joint 7th Human Genome Organization Pacific meeting and the 8th Asia-Pacific Conference on Human Genetics
    • Place of Presentation
      Cebu-City, Philippines
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Dose valproic acid increase survival motor reuron levels in spinal muscular atrophy partient cells.2007

    • Author(s)
      Gunadi,
    • Organizer
      The 3rd Indonesia Pediatrics
    • Place of Presentation
      Indonesia
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] SMN2遺伝子が3コピーあった脊髄性筋萎縮症3型の2歳女児例2007

    • Author(s)
      梶本まどか, 末永尚子, 市山高志, 古川漸, 西野一三, 西尾久英
    • Organizer
      第49回日本小児神経学会総会
    • Place of Presentation
      大阪
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Dose valproic acid increase survival motor reuron levels in spinal muscular atrophy partient cells2007

    • Author(s)
      Gunadi
    • Organizer
      The 3rd Indonesia Pediatrics Meeting
    • Place of Presentation
      Yogyakarta, Indonesia
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] A novel mutation at N-terminal of SMN tudor domain inhibits its interaction with target proteins.2006

    • Author(s)
      Nishio H, Lee MJ, Kotani T, Sutomo R, interaction with target proteins. Nishio H, Lee MJ, Kotani T, Sutomo R, Sadewa AH, Sasongko TH, Gunadi, Matsuo M.
    • Organizer
      The American Society of Human Genetics 56th Annual Meeting,
    • Place of Presentation
      New Orleans
    • Year and Date
      2006-11-05
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 先天性白内障を合併した脊髄性筋萎縮症の男児例(会議録/症例報告)2006

    • Author(s)
      牧野泰子, 村田水紀, 幸脇正典, 小山典久, 横地健治, 今井一徳, 河辺義和, 西尾久英, 西野一三
    • Organizer
      第25回日本小児神経学会東海地方会
    • Place of Presentation
      名古屋
    • Year and Date
      2006-07-22
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] A novel mutation at N-terminal of SMN tudor domain inhibits its interaction with target proteins2006

    • Author(s)
      Nishio, H, Lee, MJ, Kotani, T, Sutomo, R, Sadewa, AH, Sasongko, TH, Gunadi
    • Organizer
      The American Society of Human Genetics 56th Annual Meeting
    • Place of Presentation
      New Orleans, Louisiana
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-03-31   Modified: 2016-04-21  

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