title: β2 Agonists enhance the efficacy of simultaneous enzyme replacement therapy in murine Pompe disease.
abstract: 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.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. koebe001@mc.duke.edu
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Dai
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.forename: Priya S
authors.initials: PS
authors.lastname: Kishnani
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage; D000420:Albuterol / Q000008:administration & dosage; D000818:Animals; D002976:Clenbuterol / Q000008:administration & dosage; D004195:Disease Models, Animal; D004357:Drug Synergism; D056947:Enzyme Replacement Therapy; D006009:Glycogen Storage Disease Type II / Q000628:therapy*; D006801:Humans; D051379:Mice; D017527:Receptor, IGF Type 2 / Q000235:genetics / Q000378:metabolism*; D000520:alpha-Glucosidases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D017527:Receptor, IGF Type 2; D000520:alpha-Glucosidases; D000420:Albuterol; D002976:Clenbuterol