筋ジストロフィーに対するアンチセンス治療における線維化因子の動態に関する研究

• 研究課題/領域番号: 23591495
• 研究種目: 基盤研究(C)
• 配分区分: 基金
• 応募区分: 一般
• 研究分野: 小児科学
• 研究機関: 神戸大学
• 研究代表者: 竹島 泰弘 神戸大学, 医学(系)研究科(研究院), 教授 (40281141)
• 研究分担者: 八木 麻理子 神戸大学, 大学院医学研究科, 研究員 (60362787)
• 研究期間 (年度): 2011 – 2013
• 研究課題ステータス: 完了 (2013年度)
• 配分額: 5,200千円 (直接経費: 4,000千円、間接経費: 1,200千円); 2013年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2012年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円); 2011年度: 2,470千円 (直接経費: 1,900千円、間接経費: 570千円)
• キーワード: アンチセンスオリゴヌクレオチド / 筋ジストロフィー / エクソンスキッピング / 線維化因子 / アンチセンスオリゴ

研究概要

Duchenne型筋ジストロフィー(以下DMD)に対し、アンチセンスオリゴヌクレオチド(以下AS-oligo)によってエクソンスキッピングを誘導する治療法の有効性を高めるために、本疾患における線維化および炎症の関与を検討した。エクソン45のスキッピングを誘導するAS-oligoの薬効動態を検討し、EC50が58.0nMであることが明らにした。さらに、DMD患者において炎症のマーカーである尿中のプロスタグランジンD代謝産物の排泄量が増加していることを明らかにした。これらの結果を踏まえ、DMD症例に対しAS-oligo投与を行い、一部の炎症性サイトカインにおいて改善傾向がみられることを見出した。

研究成果

• [雑誌論文] Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients (2014)
  • 著者名/発表者名: Lee T, Takeshima Y, Kusunoki N, Awano H, Yagi M, Matsuo M, and Iijima K
  • 雑誌名: J Hum Genet 巻: 59 ページ: 46-50
  • NAID: 40019946811
  • 査読あり
• [雑誌論文] Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients. (2014)
  • 著者名/発表者名: Lee T, Takeshima Y, Kusunoki N, Awano H, Yagi M, Matsuo M, Iijima K.
  • 雑誌名: J Hum Genet. 巻: 59 ページ: 46-50
  • NAID: 40019946811
  • 査読あり
• [雑誌論文] Molecular characterization of an X(p21.2;q28) chromosomal inversion in a Duchenne muscular dystrophy patient with mental retardation reveals a novel long non-coding gene on Xq28 (2013)
  • 著者名/発表者名: Tran TH, Zhang Z, Yagi M, Lee T, Awano H, Nishida A, Okinaga T, Takeshima Y, and Matsuo M
  • 雑誌名: J Hum Genet 巻: 58 ページ: 33-9
  • NAID: 10031145898
  • 査読あり
• [雑誌論文] Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular dystrophy (2013)
  • 著者名/発表者名: Yamamoto T, Tanaka H, Matsumoto K, Lee T, Awano H, Yagi M, Imanishi T, Hayashi N, Takeshima Y, Kawai H, Kawano S, and Hirata K
  • 雑誌名: Am J Cardiol 巻: 111 ページ: 902-7
  • 査読あり
• [雑誌論文] A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old (2013)
  • 著者名/発表者名: Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, and Matsuo M
  • 雑誌名: Clin Chim Acta 巻: 423 ページ: 10-4
  • 査読あり
• [雑誌論文] A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old. (2013)
  • 著者名/発表者名: Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, Matsuo M.
  • 雑誌名: Clin Chim Acta. 巻: 423 ページ: 10-4
  • 査読あり
• [雑誌論文] Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular dystrophy. (2013)
  • 著者名/発表者名: Yamamoto T, Tanaka H, Matsumoto K, Lee T, Awano H, Yagi M, Imanishi T, Hayashi N, Takeshima Y, Kawai H, Kawano S, Hirata K.
  • 雑誌名: Am J Cardiol. 巻: 111 ページ: 902-7
  • 査読あり
• [雑誌論文] Molecular characterization of an X(p21.2;q28) chromosomal inversion in a Duchenne muscular dystrophy patient with mental retardation reveals a novel long non-coding gene on Xq28. (2013)
  • 著者名/発表者名: Tran TH, Zhang Z, Yagi M, Lee T, Awano H, Nishida A, Okinaga T, Takeshima Y, Matsuo M.
  • 雑誌名: J Hum Genet. 巻: 58 ページ: 33-9
  • NAID: 10031145898
  • 査読あり
• [雑誌論文] A prostaglandin D2 metabolite is elevated in the urine of Duchenne muscular dystrophy patients and increases further from 8 years old (2013)
  • 著者名/発表者名: Taku Nakagawa, Atsuko Takeuchi, Ryohei Kakiuchi, Tomoko Lee, Mariko Yagi, Hiroyuki Awano, Kazumoto Iijima, Yasuhiro Takeshima, Yoshihiro Urade , Masafumi Matsuo
  • 雑誌名: Clinica Chimica Acta 巻: in press
  • 査読あり
• [雑誌論文] A G-to-T transversion at the splice acceptor site of dystrophin exon 14 shows multiple splicing outcomes that are not exemplified by transition mutations (2012)
  • 著者名/発表者名: Ota M, Takeshima Y, Nishida A, Awano H, Lee T, Yagi M, and Matsuo M
  • 雑誌名: Genet Test Mol Biomarkers 巻: 16 ページ: 3-8
  • 査読あり
• [雑誌論文] Optimizing RNA/ENA chimeric antisense oligonucleotides using in vitro splicing (2012)
  • 著者名/発表者名: Takeshima Y, Yagi M, and Matsuo M
  • 雑誌名: Methods Mol Biol 巻: 867 ページ: 131-41
  • 査読あり
• [雑誌論文] Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers (2012)
  • 著者名/発表者名: Malueka RG, Takaoka Y, Yagi M, Awano H, Lee T, Dwianingsih EK, Nishida A, Takeshima Y, and Matsuo M
  • 雑誌名: BMC Genet 巻: 13 ページ: 23-23
  • 査読あり
• [雑誌論文] Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon. (2012)
  • 著者名/発表者名: Solyom S, Ewing AD, Hancks DC, Takeshima Y, Awano H, Matsuo M, Kazazian H H, Jr.
  • 雑誌名: Hum Mutat. 巻: 33(2) 号: 2 ページ: 369-71
  • DOI: 10.1002/humu.21663
  • 査読あり
• [雑誌論文] Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers (2012)
  • 著者名/発表者名: Rusdy Ghazali Malueka, Yutaka Takaoka, Mariko Yagi, Hiroyuki Awano, Tomoko Lee, Ery Kus Dwianingsih, Atsushi Nishida, Yasuhiro Takeshima, Masafumi Matsuo
  • 雑誌名: BMC Genetics 巻: 13(23) 号: 1 ページ: 23-23
  • DOI: 10.1186/1471-2156-13-23
  • 査読あり
• [雑誌論文] A G-to-T transversion at the splice acceptor site of dystrophin exon 14 shows multiple splicing outcomes that are not exemplified by transition mutations. (2012)
  • 著者名/発表者名: Ota M, Takeshima Y, Nishida A, Awano H, Lee T, Yagi M, Matsuo M.
  • 雑誌名: Genet Test Mol Biomarkers. 巻: 16 号: 1 ページ: 3-8
  • DOI: 10.1089/gtmb.2010.0276
  • 査読あり
• [雑誌論文] Categorization of 77 dystrophin exons into 5 groups by a decision tree using indexes of splicing regulatory factors as decision markers. (2012)
  • 著者名/発表者名: Malueka RG, Takaoka Y, Yagi M, Awano H, Lee T, Dwianingsih EK, Nishida A, Takeshima Y, Matsuo M.
  • 雑誌名: BMC Genet. 巻: 13 ページ: 23-23
  • 査読あり
• [雑誌論文] Optimizing RNA/ENA Chimeric Antisense Oligonucleotides Using In Vitro Splicing. (2012)
  • 著者名/発表者名: Takeshima Y, Yagi M, Matsuo M.
  • 雑誌名: Methods Mol Biol. 巻: 867 ページ: 131-41
• [雑誌論文] Antisense oligonucleotide induced dystrophin exon 45 skipping at a low half-maximal effective concentration in a cell-free splicing system (2011)
  • 著者名/発表者名: Malueka RG, Yagi M, Awano H, Lee T, Dwianingsih EK, Nishida A, Takeshima Y, and Matsuo M
  • 雑誌名: Nucleic Acid Ther 巻: 21 ページ: 347-53
  • 査読あり
• [学会発表] The carrier frequency in the mothers of 158 Japanese cases with Duchenne/Becker muscular dystrophy (2013)
  • 著者名/発表者名: Lee T, Kusunoki N, Yagi M, Takeshima Y, Matsuo M. and Iijima K
  • 学会等名: European Human Genetics Conference 2013
  • 発表場所: Paris, France
• [学会発表] Three-dimensional gait analysis of Duchenne muscular dystrophy; a trial to evaluate the therapeutic effect of RNA/ENA chimera antisense oligonucleotide that induces dystrophin exon 45 skipping (2013)
  • 著者名/発表者名: Takeshima Y, Yagi M, Lee T, Kusunoki N, Ojima I, Minami S, Asai T, Nakagawa A, Iijima K, and Matsuo M
  • 学会等名: 18th International Congress of the World Muscle Society
  • 発表場所: California, USA
• [学会発表] A prostaglandin D2 metabolite is elevated in the urine samples of patients with Duchenne muscular dystrophy (2013)
  • 著者名/発表者名: Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, and Matsuo M
  • 学会等名: 18th International Congress of the World Muscle Society
  • 発表場所: California, USA
• [学会発表] A novel splicing silencer generated by dystrophin exon 45 deletion could explain exon 44 skipping that modifies dystrophinopathy (2013)
  • 著者名/発表者名: Matsuo M, Dwianingsih EM, Malueka RG, Nishida A, Lee T, Yagi M, Iijima K, and Takeshima Y
  • 学会等名: American Society of Human Genetics, the 63^<rd> Annual Meeting
  • 発表場所: Boston, USA
• [学会発表] The carrier frequency in the mothers of 158 Japanese cases with Duchenne/Becker muscular dystrophy. (2013)
  • 著者名/発表者名: Lee T, Kusunoki N, Yagi M, Takeshima Y, Matsuo M, Iijima K.
  • 学会等名: European Human Genetics Conference 2013
  • 発表場所: Paris
• [学会発表] Three-dimensional gait analysis of Duchenne muscular dystrophy; a trial to evaluate the therapeutic effect of RNA/ENA chimera antisense oligonucleotide that induces dystrophin exon 45 skipping. (2013)
  • 著者名/発表者名: Takeshima Y, Yagi M, Lee T, Kusunoki N, Ojima I, Minami S, Asai T, Nakagawa A, Iijima K, Matsuo M.
  • 学会等名: 18th International Congress of the World Muscle Society
  • 発表場所: California
• [学会発表] A prostaglandin D2 metabolite is elevated in the urine samples of patients with Duchenne muscular dystrophy. (2013)
  • 著者名/発表者名: Nakagawa T, Takeuchi A, Kakiuchi R, Lee T, Yagi M, Awano H, Iijima K, Takeshima Y, Urade Y, Matsuo M.
  • 学会等名: 18th International Congress of the World Muscle Society
  • 発表場所: California
• [学会発表] A novel splicing silencer generated by dystrophin exon 45 deletion could explain exon 44 skipping that modifies dystrophinopathy. (2013)
  • 著者名/発表者名: Matsuo M, Dwianingsih EM, Maliueka RG, Nishida A, Lee T, Yagi M, Iijima K, Takeshima Y.
  • 学会等名: American Society of Human Genetics
  • 発表場所: Boston
• [学会発表] A small chemical, TG003, enhances skipping of mutated dystrophin exons : the third example revealing a decrease of exonic splicing enhancer density in common (2012)
  • 著者名/発表者名: Nishida A, Takeshima Y, Kataoka N, Yagi M, Awano H, Lee T, Iijima K, Hagiwara M, and Matsuo M
  • 学会等名: The American Society of Human Genetics, the 62^<nd> Annual Meeting
  • 発表場所: San Francisco, USA
• [学会発表] Dystrophin Gene Mutations in Three Dystrophynopathy Patients with Severe Cardiomyopathy. (2012)
  • 著者名/発表者名: Awano H, Lee T, Yagi M, Takeshima Y, Matsuo M, Iijima K.
  • 学会等名: Pediatric Academic Societies Annual Meeting
  • 発表場所: Boston
• [学会発表] A small chemical, TG003, enhances skipping of mutated dystrophin exons: the third example revealing a decrease of exonic splicing enhancer density in common. (2012)
  • 著者名/発表者名: Nishida A, Takeshima Y, Kataoka N, Yagi M, Awano H, Lee T, Iijima K, Hagiwara M, Matsuo M.
  • 学会等名: The American Society of Human Genetics, the 62th Annual Meeting
  • 発表場所: San Francisco
• [学会発表] Antisense RNA/ ethylene-bridged nucleic acid chimera induces exon skipping in cultured myocytes from DMD patients with 6 different deletion mutations (2011)
  • 著者名/発表者名: Yagi M, Lee T, Awano H, Takeshima Y, and Matsuo M
  • 学会等名: The American Society of Human Genetics 61st Annual Meeting
  • 発表場所: Montral, Canada
• [学会発表] Antisense RNA/Ethylene-bridged nucleic acid chimera induces exon 45 skipping in cultured myocytes from DMD patients with 6 different deletion mutations (2011)
  • 著者名/発表者名: Yagi M, Lee T, Awano H, Takeshima Y, Matsuo M
  • 学会等名: The American Society of Human Genetics 61st Annual Meeting
  • 発表場所: Montreal