title: Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in pompe mice.
abstract: Pompe disease is an autosomal recessive disorder caused by mutations in the acid-α glucosidase (GAA) gene. Lingual dysfunction is prominent but does not respond to conventional enzyme replacement therapy (ERT). Using Pompe (Gaa(-/-)) mice, we tested the hypothesis that intralingual delivery of viral vectors encoding GAA results in GAA expression and glycogen clearance in both tongue myofibers and hypoglossal (XII) motoneurons. An intralingual injection of an adeno-associated virus (AAV) vector encoding GAA (serotypes 1 or 9; 1 × 10(11) vector genomes, CMV promoter) was performed in 2-month-old Gaa(-/-) mice, and tissues were harvested 4 months later. Both serotypes robustly transduced tongue myofibers with histological confirmation of GAA expression (immunochemistry) and glycogen clearance (Period acid-Schiff stain). Both vectors also led to medullary transgene expression. GAA-positive motoneurons did not show the histopathologic features which are typical in Pompe disease and animal models. Intralingual injection with the AAV9 vector resulted in approximately threefold more GAA-positive XII motoneurons (P < 0.02 versus AAV1); the AAV9 group also gained more body weight over the course of the study (P < 0.05 versus AAV1 and sham). We conclude that intralingual injection of AAV1 or AAV9 drives persistent GAA expression in tongue myofibers and motoneurons, but AAV9 may more effectively target motoneurons.
authors: Department of Pediatrics, Division of Pulmonary Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors: Mai K
authors: MK
authors: Elmallah
authors: 1] Department of Pediatrics, Divisions of Cellular and Molecular Therapy and Pediatric Cardiology, College of Medicine, University of Florida, Gainesville, Florida, USA [2] Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
authors: Darin J
authors: DJ
authors: Falk
authors: 1] Department of Pediatrics, Divisions of Cellular and Molecular Therapy and Pediatric Cardiology, College of Medicine, University of Florida, Gainesville, Florida, USA [2] Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
authors: Sushrusha
authors: S
authors: Nayak
authors: Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA.
authors: Roland A
authors: RA
authors: Federico
authors: Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA.
authors: Milapjit S
authors: MS
authors: Sandhu
authors: Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida, USA.
authors: Amy
authors: A
authors: Poirier
authors: 1] Department of Pediatrics, Divisions of Cellular and Molecular Therapy and Pediatric Cardiology, College of Medicine, University of Florida, Gainesville, Florida, USA [2] Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA.
authors: Barry J
authors: BJ
authors: Byrne
authors: 1] Department of Physical Therapy, College of Public Health and Health Professions, University of Florida, Gainesville, Florida, USA [2] McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
authors: David D
authors: DD
authors: Fuller
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006003:Glycogen; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000520:alpha-Glucosidases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D006003:Glycogen; D000520:alpha-Glucosidases