title: Adjunctive β2-agonists reverse neuromuscular involvement in murine Pompe disease.
abstract: Pompe disease has resisted enzyme replacement therapy with acid α-glucosidase (GAA), which has been attributed to inefficient cation-independent mannose-6-phosphate receptor (CI-MPR) mediated uptake. We evaluated β2-agonist drugs, which increased CI-MPR expression in GAA knockout (KO) mice. Clenbuterol along with a low-dose adeno-associated virus vector increased Rotarod latency by 75% at 4 wk, in comparison with vector alone (P<2×10(-5)). Glycogen content was lower in skeletal muscles, including soleus (P<0.01), extensor digitorum longus (EDL; P<0.001), and tibialis anterior (P<0.05) following combination therapy, in comparison with vector alone. Glycogen remained elevated in the muscles following clenbuterol alone, indicating an adjunctive effect with gene therapy. Elderly GAA-KO mice treated with combination therapy demonstrated 2-fold increased wirehang latency, in comparison with vector or clenbuterol alone (P<0.001). The glycogen content of skeletal muscle decreased following combination therapy in elderly mice (P<0.05). Finally, CI-MPR-KO/GAA-KO mice did not respond to combination therapy, indicating that clenbuterol's effect depended on CI-MPR expression. In summary, adjunctive β2-agonist treatment increased CI-MPR expression and enhanced efficacy from gene therapy in Pompe disease, which has implications for other lysosomal storage disorders that involve primarily the brain.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Songtao
authors.initials: S
authors.lastname: Li
authors.forename: Baodong
authors.initials: B
authors.lastname: Sun
authors.forename: Mats I
authors.initials: MI
authors.lastname: Nilsson
authors.forename: Andrew
authors.initials: A
authors.lastname: Bird
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.forename: Dwight D
authors.initials: DD
authors.lastname: Koeberl
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics; D015316:Genetic Therapy; D005822:Genetic Vectors; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000503:physiopathology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D009469:Neuromuscular Junction / Q000187:drug effects*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D000520:alpha-Glucosidases / Q000235:genetics
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D000520:alpha-Glucosidases