Enzyme replacement therapy (ERT) with recombinant human (rh)
acid α-
glucosidase (GAA) has prolonged the survival of patients. However, the paucity of
cation-independent
mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up
rhGAA, correlated with a poor response to ERT by muscle in
Pompe disease.
Clenbuterol, a selective β2 receptor agonist, enhanced the CI-MPR expression in striated muscle through
Igf-1 mediated muscle
hypertrophy, which correlated with increased CI-MPR (also the
Igf-2 receptor) expression. In this study we have evaluated 4 new drugs in GAA knockout (KO) mice in combination with an adeno-associated virus (AAV) vector encoding human GAA, 3 alternative β2 agonists and
dehydroepiandrosterone (
DHEA). Mice were injected with AAV2/9-CBhGAA (1E+11 vector particles) at a dose that was not effective at clearing
glycogen storage from the heart. Heart GAA activity was significantly increased by either
salmeterol (p<0.01) or
DHEA (p<0.05), in comparison with untreated mice. Furthermore,
glycogen content was reduced in the heart by treatment with
DHEA (p<0.001),
salmeterol (p<0.05),
formoterol (p<0.01), or
clenbuterol (p<0.01) in combination with the AAV vector, in comparison with untreated GAA-KO mice. Wirehang testing revealed that
salmeterol and the AAV vector significantly increased performance, in comparison with the AAV vector alone (p<0.001). Similarly,
salmeterol with the vector increased performance significantly more than any of the other drugs. The most effective individual drugs had no significant effect in absence of vector, in comparison with untreated mice. Thus,
salmeterol should be further developed as adjunctive
therapy in combination with either ERT or gene therapy for
Pompe disease.