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

2015 Fiscal Year Final Research Report

• 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
• Keywords: ライソゾーム病

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.

Free Research Field

生化学