2007 Fiscal Year Final Research Report Summary
Development of Therapy for Spinal Muscular Atrophy Based on the Spliring Modulation Technology
| Project/Area Number |
18591151
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kobe University |
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Principal Investigator |
NISHIO Hisahide Kobe University, Graduate School of Medicine, Professor (80189258)
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| 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)
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| Project Period (FY) |
2006 – 2007
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| Keywords | spinal muscular atrophy / the SMN1 gene / the SMN2 gene / thetic exon-specific splicing activator / valproic acid |
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| 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.
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Research Products
(21 results)
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[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
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Journal Title
Ann Hum Genet 72(2)
Pages: 288-291
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
J Neurol. 80
Pages: 624-630
Description
「研究成果報告書概要(和文)」より
Peer Reviewed
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[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
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Journal Title
Pediatr Int 49(1)
Pages: 11-4
Description
「研究成果報告書概要(欧文)」より
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[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
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Journal Title
J Neurol 254(5)
Pages: 624-30
Description
「研究成果報告書概要(欧文)」より
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[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
Year and Date
20061009-13
Description
「研究成果報告書概要(欧文)」より
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[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
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