Investigation of inflammatory factors affecting the efficacy of the molecular therapies for muscular dystrophy

• Project/Area Number: 26461545
• 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, 助教 (30441273)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 筋ジストロフィー / 分子治療 / 炎症性物質 / エクソンスキッピング / アンチセンスオリゴヌクレオチド / プロスタグランジン / Duchenne型筋ジストロフィー / ジストロフィン / エクソンスキッピング誘導治療 / ナンセンス変異リードスルー誘導治療

Outline of Final Research Achievements

To enhance the efficacy of antisense oligonucleotide (AS-oligo)-mediated exon skipping therapy for Duchenne muscular dystrophy (DMD), the difference of the efficacy of the same AS-oligo among DMD cases and the involvement of inflammatory factors to exon skipping therapy were examined. At the beginning the efficacy of the AS-oligo inducing the skipping of exon 45 (AO85) was examined using cultured muscle cells of several DMD patients. In each case, exon 45 skipping was induced by AO85, as expected; however, the skipping efficacy was different from patient to patient. Furthermore, administration of AO85 to DMD cases resulted in the change of some serum inflammatory factors. These results suggested that exon skipping efficacy is modulated by some cis-element, and some inflammation factors may affect the efficacy of AS-oligo therapy.

Research Products

• [Journal Article] 2′-O-Methyl RNA/Ethylene-Bridged Nucleic Acid Chimera Antisense Oligonucleotides to Induce Dystrophin Exon 45 Skipping (2017)
  • Author(s): Tomoko Lee, Hiroyuki Awano, Mariko Yagi, Masaaki Matsumoto, Nobuaki Watanabe, Ryoya Goda, Makoto Koizumi, Yasuhiro Takeshima and Masafumi Matsuo
  • Journal Title: Genes Volume: 8 Issue: 2 Pages: 67-67
  • DOI: 10.3390/genes8020067
  • NAID: 120006373782
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] RNA/ENA chimera antisense oligonucleotide (AO85) was safely administered and shown to induce dystrophin exon 45 skipping in Duchenne muscular dystrophy patient: the first clinical study (2016)
  • Author(s): Yasuhiro Takeshima, Tomoko Lee, Hideki Shimomura, Yasuhiko Tanaka, Hiroyuki Awano, Atsushi Nishida, Isao Ojima, Satoshi Minami, Akio Nakagawa, Kazumoto Iijima, Masafumi Matsuo
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto International Conference Center（京都府京都市）
  • Year and Date: 2016-04-04
  • Int'l Joint Research
• [Presentation] A new antisense oligonucleotide composed of RNA/ENA chimera (AO85) against dystrophin exon 45 significantly increased six-minute walk distance in Duchenne muscular dystrophy (2016)
  • Author(s): Yasuhiro Takeshima, Tomoko Lee, Hideki shimomura, Yasuhiko Tanaka, Hiroyuki Awano, Atsushi Nishida, Isao Ojima, Satoshi Minami, Akio Nakagawa, Kazumoto Iijima, Masafumi Matsuo
  • Organizer: 5th International Congress of Myology
  • Place of Presentation: Lyon, France
  • Year and Date: 2016-03-14
  • Int'l Joint Research