Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.

Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-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<2×10(-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 wirehang 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 β2-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.
AuthorsSongtao Li, Baodong Sun, Mats I Nilsson, Andrew Bird, Mark A Tarnopolsky, Beth L Thurberg, Deeksha Bali, Dwight D Koeberl
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 27 Issue 1 Pg. 34-44 (Jan 2013) ISSN: 1530-6860 [Electronic] United States
PMID22993195 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Adrenergic beta-Agonists
  • Receptors, Adrenergic, beta-2
  • alpha-Glucosidases
  • Adrenergic beta-Agonists (pharmacology, therapeutic use)
  • Animals
  • Combined Modality Therapy
  • Dependovirus (genetics)
  • Genetic Therapy
  • Genetic Vectors
  • Glycogen Storage Disease Type II (drug therapy, physiopathology, therapy)
  • Mice
  • Mice, Knockout
  • Neuromuscular Junction (drug effects)
  • Receptors, Adrenergic, beta-2 (drug effects)
  • alpha-Glucosidases (genetics)

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