Salmeterol with Liver Depot Gene Therapy Enhances the Skeletal Muscle Response in Murine Pompe Disease.


Journal Article

Gene therapy for Pompe disease with adeno-associated virus (AAV) vectors has advanced into early phase clinical trials; however, the paucity of cation-independent mannose-6-phosphate receptor (CI-MPR) in skeletal muscle, where it is needed to take up acid α-glucosidase (GAA), has impeded the efficacy of Pompe disease gene therapy. Long-acting selective β2 receptor agonists previously enhanced the CI-MPR expression in muscle. In this study we have evaluated the selective β2 agonist salmeterol in GAA knockout mice in combination with an AAV vector expressing human GAA specifically in the liver. Quadriceps glycogen content was significantly decreased by administration of the AAV vector with salmeterol, in comparison with the AAV vector alone (p < 0.01). Importantly, glycogen content of the quadriceps was reduced to its lowest level by the combination of AAV vector and salmeterol administration. Rotarod testing revealed significant improvement following treatment, in comparison with untreated mice, and salmeterol improved wirehang performance. Salmeterol treatment decreased abnormalities of autophagy in the quadriceps, as shown be lower LC3 and p62. Vector administration reduced the abnormal vacuolization and accumulation of nuclei in skeletal muscle. Thus, salmeterol could be further developed as adjunctive therapy to improve the efficacy of liver depot gene therapy for Pompe disease.

Full Text

Duke Authors

Cited Authors

  • Han, S-O; Li, S; Everitt, JI; Koeberl, DD

Published Date

  • July 2019

Published In

Volume / Issue

  • 30 / 7

Start / End Page

  • 855 - 864

PubMed ID

  • 30803275

Pubmed Central ID

  • 30803275

Electronic International Standard Serial Number (EISSN)

  • 1557-7422

Digital Object Identifier (DOI)

  • 10.1089/hum.2018.197


  • eng

Conference Location

  • United States