Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease.
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Enzyme or gene replacement therapy with acid α-glucosidase (GAA) has achieved only partial efficacy in Pompe disease. We evaluated the effect of adjunctive clenbuterol treatment on cation-independent mannose-6-phosphate receptor (CI-MPR)-mediated uptake and intracellular trafficking of GAA during muscle-specific GAA expression with an adeno-associated virus (AAV) vector in GAA-knockout (KO) mice. Clenbuterol, which increases expression of CI-MPR in muscle, was administered with the AAV vector. This combination therapy increased latency during rotarod and wirehang testing at 12 wk, in comparison with vector alone. The mean urinary glucose tetrasaccharide (Glc4), a urinary biomarker, was lower in GAA-KO mice following combination therapy, compared with vector alone. Similarly, glycogen content was lower in cardiac and skeletal muscle following 12 wk of combination therapy in heart, quadriceps, diaphragm, and soleus, compared with vector alone. These data suggested that clenbuterol treatment enhanced trafficking of GAA to lysosomes, given that GAA was expressed within myofibers. The integral role of CI-MPR was demonstrated by the lack of effectiveness from clenbuterol in GAA-KO mice that lacked CI-MPR in muscle, where it failed to reverse the high glycogen content of the heart and diaphragm or impaired wirehang performance. However, the glycogen content of skeletal muscle was reduced by the addition of clenbuterol in the absence of CI-MPR, as was lysosomal vacuolation, which correlated with increased AKT signaling. In summary, β2-agonist treatment enhanced CI-MPR-mediated uptake and trafficking of GAA in mice with Pompe disease, and a similarly enhanced benefit might be expected in other lysosomal storage disorders.
enzyme replacement therapy
Adrenergic beta-2 Receptor Agonists
Glycogen Storage Disease Type II
Receptor, IGF Type 2
Published Version (Please cite this version)10.1096/fj.13-244202
Publication InfoFarah, Benjamin L; Madden, Lauran; Li, Songtao; Nance, Sierra; Bird, Andrew; Bursac, Nenad; ... Koeberl, Dwight D (2014). Adjunctive β2-agonist treatment reduces glycogen independently of receptor-mediated acid α-glucosidase uptake in the limb muscles of mice with Pompe disease. FASEB J, 28(5). pp. 2272-2280. 10.1096/fj.13-244202. Retrieved from https://hdl.handle.net/10161/10802.
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Professor of Biomedical Engineering
Bursac's research interests include: Stem cell, tissue engineering, and gene based therapies for heart and muscle regeneration; Cardiac electrophysiology and arrhythmias; Organ-on-chip and tissue engineering technologies for disease modeling and therapeutic screening; Small and large animal models of heart and muscle injury, disease, and regeneration. The focus of my research is on application of pluripotent stem cells, tissue engineering, and gene therapy technologies for: 1) basic s
Professor of Pediatrics
The focus of our research has been the development of gene therapy with adeno-associated virus (AAV) vectors, most recently by genome editing with CRISPR/Cas9. We have developed gene therapy for inherited disorders of metabolism, especially glycogen storage disease (GSD) and phenylketonuria (PKU). 1) GSD type Ia: Glucose-6-phosphatase (G6Pase) deficient animals provide models for developing new therapy for GSD type Ia, although early mortality complicates research with both
Professor of Medicine
Professor of Pediatrics
As a clinical biochemical geneticist and a director of the Duke Biochemical Genetics laboratory, my research interests are focused on improving laboratory diagnostics for rare inherited disorders of metabolism. I am actively involved in the development of assays using mass spectrometry and other analytical techniques. My current research on biomarkers for lysosomal storage disorders, such as Fabry and Pompe disease and the mucopolysaccharidoses includes monitoring the response to novel ther
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