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


Autoria(s): Han, SO; Li, S; Koeberl, DD
Cobertura

United States

Data(s)

01/05/2016

Resumo

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.

Formato

35 - 40

Identificador

http://www.ncbi.nlm.nih.gov/pubmed/27017193

S1096-7192(16)30025-7

Mol Genet Metab, 2016, 118 (1), pp. 35 - 40

http://hdl.handle.net/10161/12057

1096-7206

Idioma(s)

eng

Relação

Mol Genet Metab

10.1016/j.ymgme.2016.03.006

Palavras-Chave #Adeno-associated virus vector #Enzyme replacement therapy #Glycogen storage disease #Mannose-6-phosphate receptor #Pompe disease
Tipo

Journal Article