title: Glycogen storage in multiple muscles of old GSD-II mice can be rapidly cleared after a single intravenous injection with a modified adenoviral vector expressing hGAA.
abstract: BACKGROUND
  Glycogen storage disease II (GSD-II) is an autosomal recessive lysosomal storage disease, due to acid-alpha-glucosidase (GAA) deficiency. The disease is characterized by massive glycogen accumulation in the cardiac and skeletal muscles. There is early onset (infantile, also known as Pompe disease) as well as late onset (juvenile and adult) forms of GSD-II. Few studies have been published to date that have explored the consequences of delivering a potential therapy to either late onset GSD-II subjects, and/or early onset patients with long-established muscle pathology. One recent report utilizing GAA-KO mice transgenically expressing human GAA (hGAA) suggested that long-established disease in both cardiac and skeletal muscle is likely to prove resistant to therapies. To investigate the potential for disease reversibility in old GSD-II mice, we studied their responsiveness to exogenous hGAA exposure via a gene therapy approach that we have previously shown to be efficacious in young GAA-KO mice.
  
  
  METHODS
  An [E1-, polymerase-] adenoviral vector encoding hGAA was intravenously injected into two groups of aged GAA-KO mice; GAA expression and tissue glycogen reduction were evaluated.
  
  
  RESULTS
  After vector injection, we found that extremely high amounts of hepatically secreted hGAA could be produced, and subsequently taken up by multiple muscle tissues in the old GAA-KO mice by 17 days post-injection (dpi). As a result, all muscle groups tested in the old GAA-KO mice showed significant glycogen reductions by 17 dpi, relative to that of age-matched, but mock-injected GAA-KO mice. For example, glycogen reduction in heart was 84%, in quadriceps 46%, and in diaphragm 73%. Our data also showed that the uptake and the subsequent intracellular processing of virally expressed hGAA were not impaired in older muscles.
  
  
  CONCLUSIONS
  Overall, the previously reported 'resistance' of old GAA-KO muscles to exogenous hGAA replacement approaches can be rapidly overcome after a single intravenous injection with a modified adenoviral vector expressing hGAA.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Xu
authors.forename: Enyu
authors.initials: E
authors.lastname: Ding
authors.forename: Felicia
authors.initials: F
authors.lastname: Migone
authors.forename: Delila
authors.initials: D
authors.lastname: Serra
authors.forename: Ayn
authors.initials: A
authors.lastname: Schneider
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D000256:Adenoviridae; D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D005087:Glucan 1,4-alpha-Glucosidase / Q000097:blood / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006009:Glycogen Storage Disease Type II / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D006652:Histological Techniques; D051379:Mice; D008822:Mice, Transgenic; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D000520:alpha-Glucosidases
chemical_list: D006003:Glycogen; D000520:alpha-Glucosidases; D005087:Glucan 1,4-alpha-Glucosidase