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

Abstract

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 a-glucosidase (GAA), has impeded the efficacy of Pompe disease gene therapy. Long-acting selective b2 receptor agonists previously enhanced the CI-MPR expression in muscle. In this study we have evaluated the selective b2 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.

Comparisons of Infant and Adult Mice Reveal Age Effects for Liver Depot Gene Therapy in Pompe Disease

“…Another long-acting β 2 agonist, salmeterol, improved the cardiac response to the direct transduction of striated muscle 33 . Furthermore, salmeterol improved the biochemical correction of skeletal muscle and enhanced muscle strength in combination with liver depot gene therapy 34 . Although direct transduction of muscle might provide more stable transduction, an AAV vector containing a muscle-specific promoter provoked antibody responses that interfered with the uptake of GAA in uncorrected myofibers 35 .…”

“…33 Furthermore, salmeterol improved the biochemical correction of skeletal muscle and enhanced muscle strength in combination with liver depot gene therapy. 34 Although direct transduction of muscle might provide more stable transduction, an AAV vector containing a muscle-specific promoter provoked antibody responses that interfered with the uptake of GAA in uncorrected myofibers. 35 Immunosuppression was beneficial, because glycogen clearance was clearly enhanced by treatment with a nondepleting anti-CD4 monoclonal antibody along with GAA expression in cardiac muscle.…”

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

“…More recently, to address the poor biodistribution of the agent to certain organs, including CNS studies on modifying the ERT agent have emerged (Condori et al, 2016 ) and skeletal muscle (Koeberl et al, 2011 ; Peng et al, 2017 ; Han et al, 2019 ). To investigate the potential of large-molecular weight compounds to treat neurological disorders, novel approaches are required to surmount the BBB.…”

Preclinical Research in Glycogen Storage Diseases: A Comprehensive Review of Current Animal Models

“…For muscle targeted systemic gene transfer, various studies using different AAV and different muscle promoters have been performed [ 156 , 159 , 160 , 161 , 162 , 163 , 164 ] in 6 neo /6 neo mice leading to similar findings of improvement of the respiratory phenotype, muscle strength and morphology, although there was not a complete glycogen correction and not in all studies [ 165 ]. For liver targeted systemic transfer various studies using different AAV and liver-specific promoters have been tried too in mice models, showing an efficient liver transduction with 10 to 100 times lower AAV vector doses needed [ 147 , 148 , 152 , 166 , 167 , 168 , 169 , 170 , 171 , 172 ]. In this case, the effects are mainly based on cross-correction, as GAA enzyme is only produced by hepatocytes, secreted to the circulation and taken up by target cells, showing a glycogen clearance in the heart and diaphragm but not as much in the skeletal muscle probably due to an insufficient native secretion of GAA.…”