Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease

Pompe disease has resisted enzyme replacement therapy with acid alpha-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated beta 2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P < 2 x 10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P < 0.01), extensor digitorum longus (EDL; P < 0.001), and tibialis anterior (P < 0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wire-hang latency, in comparison with vector or clenbuterol alone (P < 0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P < 0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive beta 2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.-Li, S., Sun, B., Nilsson, M. I., Bird, A., Tarnopolsky, M. A., Thurberg, B. L., Bali, D., Koeberl, D. D. Adjunctive beta 2-agonists reverse neuromuscular involvement in murine Pompe disease. FASEB J. 27, 34-44 (2013). www.fasebj.org