Development of Antisense Mediated Therapy for Exons Duplication in Duchenne Muscular Dystrophy.

• Project/Area Number: 25460666
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: National Center of Neurology and Psychiatry
• Principal Investigator: SAITO Takashi 国立研究開発法人国立精神・神経医療研究センター, 遺伝子疾患治療研究部, 客員研究員 (40625969)
• Co-Investigator(Kenkyū-buntansha): NAGATA Tetsuya 国立精神・神経医療研究センター神経研究所, 遺伝子疾患治療研究部, 客員研究員 (50362976) ; TAKEDA Shin'ichi 国立精神・神経医療研究センター神経研究所, 遺伝子疾患治療研究部, 部長 (90171644)
• Research Collaborator: AOKI Yoshitsugu ; TANIHATA Jun ; NAKAMURA Akinori ; MASUDA Satoru ; MOTOHASHI Yuko ; YOKOTA Toshifumi
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 応用薬理学 / 遺伝子診断・治療 / 筋ジストロフィー / ジストロフィン / 重複変異 / アンチセンス / エクソン・スキップ

Outline of Final Research Achievements

Duchenne muscular dystrophy is a disorder with dystrophin deficiency caused by DMD gene mutation and its 10% patients have exon duplication mutation. This study explored the feasibility of exon-skipping therapy for exon duplication in DMD gene. Cells from DMD patient having exon 8/9 duplication were treated by antisense targeting exon 6/7/8. A restoration to the in-frame mutation and a recovery of dystrophin were observed; suggesting the feasibility of exon-skipping therapy for exon duplication. However, it was not identified what is the best method to achieve stable and reproducible results; and further studies are required.

Research Products

• [Journal Article] Deletion of exons 3-9 encompassing a mutational hot spot in the DMD gene presents an asymptomatic phenotype, indicating a target region for multiexon skipping therapy. (2016)
  • Author(s): Nakamura A, Fueki N, Shiba N, Motoki H, Miyazaki D, Nishizawa H, Echigoya Y, Yokota T, Aoki Y, Takeda S.
  • Journal Title: J Hum Genet Volume: 61 Issue: 7 Pages: 663-667
  • DOI: 10.1038/jhg.2016.28
  • NAID: 40020884111
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. (2015)
  • Author(s): Echigoya Y, Aoki Y, Miskew B, Panesar D, Touznik A, Nagata T, Tanihata J, Nakamura A, Nagaraju K, Yokota T
  • Journal Title: Mol Ther Nucleic Acids Volume: 4 Pages: e225-e225
  • DOI: 10.1038/mtna.2014.76
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. (2014)
  • Author(s): Hathout Y, Marathi RL, Rayavarapu S, Zhang A, Brown KJ, Seol H, Gordish-Dressman H, Cirak S, Bello L, Nagaraju K, Partridge T, Hoffman EP, Takeda S, Mah JK, Henricson E, McDonald C
  • Journal Title: Human Molecular Genetics Volume: 23 Issue: 24 Pages: 6458-69
  • DOI: 10.1093/hmg/ddu366
  • Peer Reviewed
• [Journal Article] 選択的スプライシングを調節するアンチセンス医薬品の開発について (2014)
  • Author(s): 齊藤 崇、武田伸一
  • Journal Title: 医薬品医療機器レギュラトリーサイエンス Volume: 45 Pages: 23-32
  • NAID: 40019946374
• [Journal Article] Identification of a Duplication Breakpoint in the DMD Gene Using Array Comparative Genomic Hybridization (2013)
  • Author(s): Saito T, Ishigaki K, Murakami T, Sato T, Kajino S, Takeda S, Osawa M
  • Journal Title: Journal of Tokyo Women's Medical College Volume: 83(E1)
  • NAID: 110009559372
  • Peer Reviewed
• [Journal Article] Highly efficient in vivo delivery of PMO into regenerating myotubes and rescue in laminin-α2 chain-null congenital muscular dystrophy mice (2013)
  • Author(s): Aoki Y, Nagata T, Yokota T, Nakamura A, Wood MJ, Partridge T, Takeda S
  • Journal Title: Hum Mol Genet Volume: 22 Issue: 24 Pages: 4914-4928
  • DOI: 10.1093/hmg/ddt341
  • Peer Reviewed
• [Journal Article] Characteristics of Japanese Duchenne and Becker muscular dystrophy patients in a novel Japanese national registry of muscular dystrophy (Remudy). (2013)
  • Author(s): Nakamura H, Kimura E†, Mori-Yoshimura M, Komaki H, Matsuda Y, Goto K, Hayashi YK, Nishino I, Takeda SI, Kawai M.
  • Journal Title: Orphanet J Rare Dis. Volume: 8(1) Issue: 1 Pages: 60-60
  • DOI: 10.1186/1750-1172-8-60
  • Peer Reviewed
• [Journal Article] Prednisolone improves walking in Japanese Duchenne muscular dystrophy patients (2013)
  • Author(s): Takeuchi F, Yonemoto N, Nakamura H, Shimizu R, Komaki H, Mori-Yoshimura M, Hayashi YK, Nishino I, Kawai M, Kimura E, Takeda S
  • Journal Title: J Neurol Volume: 260 Issue: 12 Pages: 3023-3029
  • DOI: 10.1007/s00415-013-7104-y
  • Peer Reviewed
• [Presentation] First-in-Human Study of NS-065/NCNP-01; the Morpholino Based Antisense Oligonucleotide for Exon 53 Skipping in Duchenne Muscular Dystrophy (2015)
  • Author(s): Saito T, Nagata T, Masuda S, Aoki Y, Suzuki M, Nakamura H, Komaki H, Takeda S
  • Organizer: American society of gene & cell therapy 18th Annual meeting
  • Place of Presentation: Hyatt Regency, New Orleans, USA
  • Year and Date: 2015-05-13
  • Int'l Joint Research
• [Presentation] DMD/BMD patient registry in Japan: Remudy. (2014)
  • Author(s): Kimura E, Nakamura H, Khayashi Y, Mori-Yoshimura M, Shimizu R, Komaki H, Nishino I, Kawai M, Takeda S
  • Organizer: 13th International Congress on Neuromuscular Diseases
  • Place of Presentation: Acropolis Convention Center, Nice, France
  • Year and Date: 2014-07-05 – 2014-07-10
• [Presentation] Assessment of the Dystrophin Gene Exon 53 Skipping Using DMD Patient-Derived Fibroblasts for Exploratory Clinical Trial of Antisense Drug NS-065/NCNP-01 (2014)
  • Author(s): Saito T, Nagata T, Masuda S, Tanihata J, Ohata M, Tamaura A, Kanazawa M, Minami N, Goto K, Hayashi Y, Iwasawa K, Tatezawa K, Fukuda K, Mizutani T, Shimizu R, Suzuki M, Yamaguchi K, Tachimori H, Nishino I, Goto Y, Komaki H, Takeda S
  • Organizer: American society of gene & cell therapy 17th Annual meeting
  • Place of Presentation: Marriott Wardman Park, Washington, DC, USA
  • Year and Date: 2014-05-20 – 2014-05-23
• [Presentation] Exon Skipping Approach To Duchenne Muscular Dystrophy (2013)
  • Author(s): Takeda S
  • Organizer: The 12th Annual Asian and Oceanian Myology Center (AOMC)Scientific Meeting
  • Place of Presentation: Xian,China
  • Invited
• [Presentation] Exploratory Study of Exon 53 Skipping Drug NS-065/NCNP-01 in Duchenne Muscular Dystrophy (2013)
  • Author(s): Takeda S
  • Organizer: Action Duchenne 12nd International Conference
  • Place of Presentation: London, UK
  • Invited
• [Presentation] 筋ジストロフィーに対するアンチセンス核酸医薬品の開発 (2013)
  • Author(s): 武田伸一
  • Organizer: 第29回日本DDS学会学術集会
  • Place of Presentation: 京都テルサ，京都市
  • Invited
• [Presentation] 医薬品関連・薬事戦略相談を受けて - モルフォリノ核酸：デュシェンヌ型筋ジストロフィー（DMD）の治療 (2013)
  • Author(s): 武田伸一
  • Organizer: PMDA薬事戦略フォーラム
  • Place of Presentation: 全社協・灘尾ホール，千代田区
  • Invited
• [Presentation] Duchenne 型筋ジストロフィーに対するエクソン53 スキップによる早期探索的臨床試験 (2013)
  • Author(s): 永田哲也，齊藤 崇，清水玲子，小牧宏文，武田伸一
  • Organizer: 第31回日本神経治療学会総会
  • Place of Presentation: 東京ドームホテル，千代田区
• [Book] 遺伝子治療・診断の最先端技術と新しい医薬品・診断薬の開発 (2014)
  • Author(s): 齊藤 崇（情報技術協会 編）
  • Total Pages: 600
  • Publisher: 技術情報協会
• [Book] 筋疾患診療ハンドブック (2013)
  • Author(s): 永田哲也, 武田伸一（内野 誠 監）
  • Total Pages: 206
  • Publisher: 中外医学社