Non-invasive system for predicting effectiveness of the exon skipping therapy for muscular dystrophy

• Project/Area Number: 17K10087
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Hyogo Medical University
• Principal Investigator: Yasuhiro Takeshima 兵庫医科大学, 医学部, 教授 (40281141)
• Co-Investigator(Kenkyū-buntansha): 李 知子 兵庫医科大学, 医学部, 助教 (10596042) ; 下村 英毅 兵庫医科大学, 医学部, 講師 (30441273) ; 三崎 真生子 兵庫医科大学, 医学部, 助教 (50595048)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: muscular dystrophy / molecular therapy / splicing / exon skipping / 筋ジストロフィー / 分子治療 / エクソンスキッピング / 次世代シークエンサー / 小児神経学

Outline of Final Research Achievements

Modulation of splicing with antisense oligonucleotide that convert out-of-frame dystrophin mRNA into in-frame has been developed as a novel therapy for Duchenne muscular dystrophy. However, the effectiveness is different among patients, which disturb the development of antisense oligonucleotide therapy. To establish the non-invasive system for predicting effectiveness of the splicing modulation therapy for muscular dystrophy, gene mutation and splicing pattern of patients were analyzed, and artificial mutant genes were introduced to the cultured cells.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、アンチセンスオリゴヌクレオチドによりスプライシングを制御する治療法において、事前に、非侵襲的にその有効性を予測するシステムを開発し得る可能性がある。このようなシステムを応用することにより、より的確に本治療法を臨床応用できるようになり、デュシェンヌ型筋ジストロフィーに対するアンチセンスオリゴヌクレオチド治療の開発をさらに推進できる可能性がある。

Research Products

• [Journal Article] Two closely spaced mutations in cis result in Ullrich congenital muscular dystrophy (2019)
  • Author(s): Shimomura Hideki、Lee Tomoko、Tanaka Yasuhiko、Awano Hiroyuki、Itoh Kyoko、Nishino Ichizo、Takeshima Yasuhiro
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 21-21
  • DOI: 10.1038/s41439-019-0052-z
  • NAID: 120006644105
  • Peer Reviewed / Open Access
• [Journal Article] RNA sequencing reveals abnormal LDB3 splicing in sudden cardiac death (2019)
  • Author(s): Yamamoto Takuma、Miura Aya、Itoh Kyoko、Takeshima Yasuhiro、Nishio Hajime
  • Journal Title: Forensic Science International Volume: 302 Pages: 109906-109906
  • DOI: 10.1016/j.forsciint.2019.109906
  • Peer Reviewed
• [Journal Article] Ambulatory capacity in Japanese patients with Duchenne muscular dystrophy (2018)
  • Author(s): Awano H, Itoh C, Takeshima Y, Lee T, Matsumoto M, Kida A, Kaise T, Suzuki T, Matsuo M.
  • Journal Title: Brain and Development Volume: 40 Issue: 6 Pages: 465-472
  • DOI: 10.1016/j.braindev.2018.02.011
  • Peer Reviewed
• [Journal Article] Patients with Duchenne muscular dystrophy are significantly shorter than those with Becker muscular dystrophy, with the higher incidence of short stature in Dp71 mutated subgroup (2017)
  • Author(s): Matsumoto M, Awano H, Lee T, Takeshima Y, Matsuo M, Iijima K.
  • Journal Title: Neuromuscular disorders Volume: 27 Issue: 11 Pages: 1023-1028
  • DOI: 10.1016/j.nmd.2017.06.007
  • Peer Reviewed
• [Journal Article] Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy. (2017)
  • Author(s): Yamamoto T, Taniguchi-Ikeda M, Awano H, Matsumoto M, Lee T, Harada R, Imanishi T, Hayashi N, Sakai Y, Morioka I, Takeshima Y, Iijima K, Saegusa J, Toda T.
  • Journal Title: Brain and Development Volume: 39 Issue: 10 Pages: 861-868
  • DOI: 10.1016/j.braindev.2017.05.008
  • Peer Reviewed / Open Access
• [Presentation] ジストロフェン遺伝子内に切断点を有するＸ染色体-常染色体均衡型転座によるデュシェンヌ型筋ジストロフィー女児 (2019)
  • Author(s): 李 知子, 底田 辰之, 三﨑 真生子, 下村 英毅, 奥野 美佐子, 竹島 泰弘
  • Organizer: 第60回日本人類遺伝学会
• [Presentation] 家族歴のない高ＣＫ血症女児の臨床背景の検討 (2019)
  • Author(s): 李 知子, 徳永 沙知, 牟禮 慎子, 三﨑 真生子, 下村 英毅, 西野 一三, 伊東 恭子, 竹島 泰弘
  • Organizer: 第61回日本小児神経学会学術集会
• [Presentation] A manifesting carrier of Duchenne Muscular Dystrophy with a balanced X-autosome translocation with a breakpoint in the dystrophin gene (2019)
  • Author(s): Lee T., Sokoda T., Misaki M., Shimomura H., Takeshima Y.
  • Organizer: 24th International Annual Congress of the World Muscle Society
  • Int'l Joint Research
• [Presentation] Clinical background of hyper-creatine-kinase-emia girls without a family history of genetic muscular diseases (2019)
  • Author(s): Tamoko L., Tokunaga S.,, Mure C., Misaki M., Shimomura H., Nishino I., Itoh K., Takeshima Y.
  • Organizer: EUROPEAN HUMAN GENETICS CONFERENCE 2019
  • Int'l Joint Research
• [Presentation] 家族歴のない無症候性高CK血症女児の検討 (2018)
  • Author(s): 李知子、三崎真生子、下村英毅、伊東恭子、竹島泰弘
  • Organizer: 第121回日本小児科学会学術集会
• [Presentation] 次世代シークエンサーを用いた遺伝子解析によりCalpain-3遺伝子変異を同定した筋症状のない高CK血症女児 (2018)
  • Author(s): 李知子、西岡 隆文、三崎真生子、下村英毅、竹島泰弘
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 新規変異を同定した重症型LMNA-related congenital muscular dystrophyの一例 (2018)
  • Author(s): 李 知子、下村英毅、牟禮慎子、三崎真生子、香田 翼、柴田暁男、
  • Organizer: 第60回日本小児神経学会学術集会
• [Presentation] 新規変異を同定した重症型LMNA-related congenital muscular dystrophyの一例 (2018)
  • Author(s): 李 知子、下村英毅、牟禮慎子、三崎真生子、香田 翼、柴田暁男、川本久美、岡田陽子、小泉真琴、伊東恭子、竹島泰弘
  • Organizer: 日本小児神経学会