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Salmeterol enhances the cardiac response to gene therapy in Pompe disease.

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Date
2016-05
Authors
Han, Sang-Oh
Li, Songtao
Koeberl, Dwight D
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Abstract
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.
Type
Journal article
Subject
Adeno-associated virus vector
Enzyme replacement therapy
Glycogen storage disease
Mannose-6-phosphate receptor
Pompe disease
Animals
Clenbuterol
Dehydroepiandrosterone
Dependovirus
Disease Models, Animal
Enzyme Replacement Therapy
Genetic Therapy
Genetic Vectors
Glycogen
Glycogen Storage Disease Type II
Humans
Mice
Mice, Knockout
Myocardium
Salmeterol Xinafoate
alpha-Glucosidases
Permalink
https://hdl.handle.net/10161/12057
Published Version (Please cite this version)
10.1016/j.ymgme.2016.03.006
Publication Info
Han, Sang-Oh; Li, Songtao; & Koeberl, Dwight D (2016). Salmeterol enhances the cardiac response to gene therapy in Pompe disease. Mol Genet Metab, 118(1). pp. 35-40. 10.1016/j.ymgme.2016.03.006. Retrieved from https://hdl.handle.net/10161/12057.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Koeberl

Dwight D. Koeberl

Professor of Pediatrics
As a physician-scientist practicing clinical and biochemical genetics, I am highly motivated to seek improved therapy for my patients with inherited disorders of metabolism. 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
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