A beta-blocker, propranolol, decreases the efficacy from enzyme replacement therapy in Pompe disease

作者：Han Sang oh; Pope Rand; Li Songtao; Kishnani Priya S; Steet Richard^*; Koeberl Dwight D^*

来源：Molecular Genetics and Metabolism, 2016, 117(2): 114-119.

DOI：10.1016/j.ymgme.2015.09.012

• Lysosomal storage disorder (LSD)
• Pompe disease
• Acid alpha-glucosidase (GAA)
• Enzyme replacement therapy (ERT)
• beta-Blocker
• Propranolol

Enzyme replacement therapy (ERT) with recombinant human acid ca.-glucosidase (rhGAA) fails to completely reverse muscle weakness in Pompe disease. beta 2-agonists enhanced ERT by increasing receptor-mediated uptake of rhGAA in skeletal muscles.
Purpose: To test the hypothesis that a beta-blocker might reduce the efficacy of ERT, because the action of beta-blockers opposes those of beta 2-agonists.
Methods: Mice with Pompe disease were treated with propranolol (a beta-blocker) or clenbuterol in combination with ERT, or with ERT alone.
Results: Propranolol-treated mice had decreased weight gain (p < 0.01), in comparison with clenbuterol-treated mice. Left ventricular mass was decreased (and comparable to wild-type) in ERT only and clenbuterol-treated groups of mice, and unchanged in propranolol-treated mice. GM activity increased following either clenbuterol or propranolol in skeletal muscles. However, muscle glycogen was reduced only in clenbuterol-treated mice, not in propranolol-treated mice. Cell-based experiments confirmed that propranolol reduces uptake of rhGAA into Pompe fibroblasts and also demonstrated that the drug induces intracellular accumulation of glycoproteins at higher doses.
Conclusion: Propranolol, a commonly prescribed beta-blocker, reduced weight, increased left ventricular mass and decreased glycogen clearance in skeletal muscle following ERT. beta-Blockers might therefore decrease the efficacy from ERT in patients with Pompe disease.

• 出版日期2016-2