β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.

Published

Journal Article

Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) has improved clinical outcomes in patients with Pompe disease; however, the response of skeletal muscle and the central nervous system to ERT has been attenuated. The poor response of skeletal muscle to ERT has been attributed to the low abundance of the cation-independent mannose-6-phosphate receptor (CI-MPR), which mediates receptor-mediated uptake of rhGAA. Hence the ability of adjunctive therapy with β2-agonists to increase CI-MPR expression in skeletal muscle was evaluated during ERT in murine Pompe disease with regard to reversal of neuromuscular involvement. Mice with Pompe disease were treated with weekly rhGAA injections (20 mg/kg) and a selective β2-agonist, either albuterol (30 mg/l in drinking water) or low-dose clenbuterol (6 mg/l in drinking water). Biochemical correction was enhanced by β2-agonist treatment in both muscle and the cerebellum, indicating that adjunctive therapy could enhance efficacy from ERT in Pompe disease with regard to neuromuscular involvement. Intriguingly, clenbuterol slightly reduced muscle glycogen content independent of CI-MPR expression, as demonstrated in CI-MPR knockout/GAA knockout mice that were otherwise resistant to ERT. Thus, adjunctive therapy with β2 agonists might improve the efficacy of ERT in Pompe disease and possibly other lysosomal storage disorders through enhancing receptor-mediated uptake of recombinant lysosomal enzymes.

Full Text

Duke Authors

Cited Authors

  • Koeberl, DD; Li, S; Dai, J; Thurberg, BL; Bali, D; Kishnani, PS

Published Date

  • February 2012

Published In

Volume / Issue

  • 105 / 2

Start / End Page

  • 221 - 227

PubMed ID

  • 22154081

Pubmed Central ID

  • 22154081

Electronic International Standard Serial Number (EISSN)

  • 1096-7206

Digital Object Identifier (DOI)

  • 10.1016/j.ymgme.2011.11.005

Language

  • eng

Conference Location

  • United States