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.