Salmeterol enhances the cardiac response to gene therapy in Pompe disease.
Repository Usage Stats
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.
SubjectAdeno-associated virus vector
Enzyme replacement therapy
Glycogen storage disease
Disease Models, Animal
Enzyme Replacement Therapy
Glycogen Storage Disease Type II
Published Version (Please cite this version)10.1016/j.ymgme.2016.03.006
Publication InfoHan, SO; Koeberl, Dwight D; & Li, S (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 http://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.
More InfoShow full item record
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
Showing items related by title, author, creator, and subject.
Time trends of incidence of age-associated diseases in the US elderly population: Medicare-based analysis. Akushevich, Igor; Arbeev, Konstantin; Kravchenko, J; Ukraintseva, Svetlana; Yashin, Anatoli I (Age Ageing, 2013-07)OBJECTIVES: time trends of age-adjusted incidence rates of 19 ageing-related diseases were evaluated for 1992-2005 period with the National Long Term Care Survey and the Surveillance, Epidemiology and End RESULTS Registry ...
Austin, SL; Brooks, ED; Fyfe, JC; Kishnani, Priya Sunil; Sun, Baodong; Thurberg, BL; Yi, Haiqing; ... (8 authors) (Comp Med, 2016-02)Glycogen storage disease type IIIa (GSD IIIa) is caused by a deficiency of glycogen debranching enzyme activity. Hepatomegaly, muscle degeneration, and hypoglycemia occur in human patients at an early age. Long-term complications ...
Akushevich, Igor; Arbeev, Konstantin; Kravchenko, J; Kulminski, Alexander; Ukraintseva, Svetlana; Yashin, Anatoli I (Exp Gerontol, 2013-12)Multi-morbidity is common among older adults; however, for many aging-related diseases there is no information for U.S. elderly population on how earlier-manifested disease affects the risk of another disease manifested ...