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Development of a new treatment with splicing modulators for spinal muscular atrophy

Research Project

Project/Area Number 15591106
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

NSIHIO Hisahide  Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80189258)

Co-Investigator(Kenkyū-buntansha) MATUO Masahumi  Kobe University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (10157266)
TAKESIMA Ysuhiro  Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (40281141)
LEE Miyojin  Kobe University, Graduate School of Medicine, Assistant Professor, 大学院・医学系研究科, 講師 (20273766)
AYAKI Hitosi  Kobe University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (80222701)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordsspinal muscular atrophy / the SMN1 gene / the SMN2 gene / hnRNP C1 / C2 / in vitro splicing assay / peptide nucleic acid
Research Abstract

1 (Purpose) The SMN1 gene is a responsible gene for the most common form of spinal muscular atrophy (SMA). The SMN2 gene is an almost identical gene to SMN1 and codes the same protein as SMN1 does. However, main product of SMN1 is a transcript including exon 7, while that of SMN2 is a transcript lacking exon7. That is the reason why SMN2 cannot compensate the loss of SMN1 in most SMA patients. A single nucleotide change in exon 7, 6C in SMN1 and 6T in SMN2, makes the splicing difference between them. The purpose of the study is to clarify the inclusion mechanism of exon 7 into the transcript of SMN1.
2 (Identification of SMN1 pre-mRNA binding proteins) To obtain the SMN1 pre-mRNA proteins, HeLa cell nuclear extract proteins bound to fluorescent die-labeled RNA probe were isolated by gel-shift method. Subsequent mass-spectrometry analysis proved that the isolated proteins were mixture of hnRNPC1/C2.
3 (In vitro splicing assay) In vitro splicing assay with mini-genes with SMN1 or SMN2 exon 7 sequences was performed. The presence of anti- hnRNPC1/C2 antibody reduced dose-dependently the splicing efficiency with SMN1 mini-gene, but did not influence on the efficiency of SMN2 mini-gene. The findings suggested that hnRNPC1/C2 has a specific role in the exon 7 inclusion into SMN1 transcript.
4 (Splicing modulation by PNA) A peptide nucleic acid (PNA) with SMN2 exon 7 binding domain and serine-arginine repeat domain was synthesized. The presence of the synthesized PNA facilitated in vitro splicing reaction of the SMN2 mini-gene. The synthesized PNA may also facilitate in the cells a transcription of full-length SMN2 mRNA to produce functional SMN protein, which suggests a splicing modulation therapy for SMA patients.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report

Research Products

(8 results)

All 2004 2003 Other

All Journal Article (7 results) Publications (1 results)

  • [Journal Article] Significant increase in the number of the SMN2 gene copies in an adult-onset type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene2004

    • Author(s)
      Yamashita M
    • Journal Title

      Eur Neurol. 第52巻・第2号

      Pages: 101-106

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significant increase in the number of the SMN2 gene copies in an adult-onset type III spinal muscular atrophy patient with homozygous deletion of the NAIP gene2004

    • Author(s)
      Yamashita, M
    • Journal Title

      Eur Neurol 52-2

      Pages: 101-106

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Significant Increase in the Number of the SMN2 Gene Copies in an Adult-Onset Type III Spinal Muscular Atrophy Patient with Homozygous Deletion of the NAIP Gene.2004

    • Author(s)
      Yamashita M
    • Journal Title

      Eur Neurol. 第52巻・第2号

      Pages: 101-106

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Delection to the SMN1 and NAIP Genes in Vietnamese Patients with Spinal Muscular Atrophy2003

    • Author(s)
      Bach ND
    • Journal Title

      Kobe Journal of Medical Sciences 第49巻・第3号

      Pages: 55-58

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genetically confirmed spinal muscular atrophy type 3 with epilepsy In a Malay patient2003

    • Author(s)
      Zilfalil BA
    • Journal Title

      Neurol J Southeast Asia 第8巻・第2号

      Pages: 113-115

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Delection to the SMN1 and NAIP Genes in Vietnamese Patients with Spinal Muscular Atrophy2003

    • Author(s)
      Bach, ND
    • Journal Title

      Kobe Journal of Medical Sciences 49-3

      Pages: 55-58

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Genetically confirmed spinal muscular atrophy type 3 with epilepsy in a Malay patient2003

    • Author(s)
      Zilfalil, BA
    • Journal Title

      Neurol J Southeast Asia 8-2

      Pages: 113-115

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Nguycn Duc Bach, Hisahide Nishio: "Dclction of the SMN1 and NAIP Genes in Vietnamese Patients with Spinal Muscular Atrophy"Kobe Journal of Medical Sciences. 第49巻3号. 55-58 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-03-31   Modified: 2016-04-21  

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