Development of enzyme enhancement therapy for Pompe disease by using proteasome inhibitor

• Project/Area Number: 24791089
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Jikei University School of Medicine
• Principal Investigator: SHIMADA YOHTA 東京慈恵会医科大学, 医学部, 助教 (20560824)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ライソゾーム病 / ポンペ病 / 先天代謝異常症

Outline of Final Research Achievements

We tried to evaluate the efficacy of enzyme enhancement therapy for Pompe disease by using proteasome inhibitor bortezomib. First, we analyzed the effect of bortezomib on several acid alpha-glucosidase (GAA) mutants in patient fibroblasts and transiently transfected cells. We found that bortezomib increases the activity of a part of chemical chaperone-unresponsive mutants as well as chemical chaperone-responsive mutants such as M519V. Next, to analyze the effect of bortezomib on animal model, we generated a novel model mouse expressing human GAA replaced methionine with valine at position 519 (M519V mice). We showed that bortezomib increases the GAA activity in heart from M519V mice, but not in skeletal muscle. These results suggest that bortezomib may be able to contribute to the improvement of GAA function in cardiac muscle in model mice.

Research Products

• [Journal Article] Proteasome Inhibitor Bortezomib Enhances the Activity of Multiple Mutant Forms of Lysosomal α-Glucosidase in Pompe Disease (2015)
  • Author(s): Shimada Y, Nishimura E, Hoshina H, Kobayashi H, Higuchi T, Eto Y, Ida H, Ohashi T
  • Journal Title: JIMD Rep. Volume: 18 Pages: 33-39
  • DOI: 10.1007/8904_2014_345
  • ISBN: 9783662448625, 9783662448632
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 新規ポンペ病モデルマウスを用いたプロテアソーム阻害剤の治療効果の検討 (2015)
  • Author(s): 嶋田洋太、石井夏実、福田隆浩、保科宙生、樋口孝、小林博司、井田博幸、大橋十也
  • Organizer: 第57回日本先天代謝異常学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2015-11-12
• [Presentation] Development of missense murine model of Pompe disease (2015)
  • Author(s): Shimada Y, Fukuda T, Nishimura E, Hoshina H, Kobayashi H, Higuchi T, Ida H, Ohashi T
  • Organizer: Annual Symposium of the Society for the Study of Inborn Errors of Metabolism
  • Place of Presentation: Lyon, France
  • Year and Date: 2015-09-01
  • Int'l Joint Research
• [Presentation] Bortezomib enhances the activity and lysosomal trafficking of multiple mutant alpha-glucosidases identified in Pompe disease. (2013)
  • Author(s): Shimada Y, Nishida H, Kobayashi H, Higuchi T, Eto Y, Ida H, Ohashi T
  • Organizer: The 3rd Asian Congress for Inborn Error of Metabolism
  • Place of Presentation: 舞浜
• [Presentation] Proteasome inhibitor improves the function and subcellular localization of mutant lysosomal alpha-glucosidase in fibroblasts from patients with Pompe disease. (2013)
  • Author(s): Shimada Y, Nishida H, Kobayashi H, Higuchi T, Eto Y, Ida H, Ohashi T
  • Organizer: 12th International Congress of Inborn Errors of Metabolism
  • Place of Presentation: Barcelona
• [Presentation] Proteasome inhibitor improves the function of mutant lysosomal alpha-glucosidase in fibroblasts from Pompe disease patient (2012)
  • Author(s): Yohta Shimada, Hikaru Nishida, Yurika Nishiyama, Hiroshi Kobayashi, Takashi Higuchi, Yoshikatsu Eto, Hiroyuki Ida, Toya Ohashi
  • Organizer: 2nd Asian Congress for Inherited Metabolic Diseases
  • Place of Presentation: Seoul, Korea
• [Presentation] ポンペ病に対する酵素安定化薬としてのプロテアソーム阻害剤の有効性の検討 (2012)
  • Author(s): 嶋田洋太、西山由梨佳、小林博司、樋口孝、衞藤義勝、井田博幸、大橋十也
  • Organizer: 第54回 日本先天代謝異常学会
  • Place of Presentation: 岐阜