Salmeterol enhances the cardiac response to gene therapy in Pompe disease.
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 articleSubject
Adeno-associated virus vectorEnzyme 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
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https://hdl.handle.net/10161/12057Published Version (Please cite this version)
10.1016/j.ymgme.2016.03.006Publication 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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Show full item recordScholars@Duke
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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