Abstract |
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.
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Authors | Songtao Li, Baodong Sun, Mats I Nilsson, Andrew Bird, Mark A Tarnopolsky, Beth L Thurberg, Deeksha Bali, Dwight D Koeberl |
Journal | FASEB 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 |
PMID | 22993195
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adrenergic beta-Agonists
- Receptors, Adrenergic, beta-2
- alpha-Glucosidases
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Topics |
- 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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