title: Physiological correction of Pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors.
abstract: Pompe disease is caused by a lack of functional lysosomal acid alpha-glucosidase (GAA) and can ultimately lead to fatal hypertrophic cardiomyopathy and respiratory insufficiency. Previously, we demonstrated the ability of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to restore the therapeutic levels of cardiac and diaphragmatic GAA enzymatic activity in vivo in a mouse model of Pompe disease. We have further characterized cardiac and respiratory function in rAAV2/1-treated animals 1 year post-treatment. Similar to the patient population, electrocardiogram measurements (P-R interval) are significantly shortened in the Pompe mouse model. In rAAV2/1-treated mice, we show a significant improvement in cardiac conductance with prolonged P-R intervals of 39.34+/-1.6 ms, as compared to untreated controls (35.58+/-0.57 ms) (P</=0.05). In addition, we note a significant decrease in cardiac left ventricular mass from 181.99+/-10.70 mg in untreated controls to 141.97+/-19.15 mg in the rAAV2/1-treated mice. Furthermore, the mice displayed an increased diaphragmatic contractile force of approximately 90% of wild-type peak forces with corresponding improved ventilation (particularly in frequency, minute ventilation, and peak inspiratory flow). These results demonstrate that in addition to biochemical and histological correction, rAAV2/1 vectors can mediate sustained physiological correction of both cardiac and respiratory function in a model of fatal cardiomyopathy and muscular dystrophy.
authors.affiliation: Powell Gene Therapy Center, University of Florida, Gainesville, Florida, USA. cmah@ufl.edu
authors.forename: Cathryn
authors.initials: C
authors.lastname: Mah
authors.forename: Christina A
authors.initials: CA
authors.lastname: Pacak
authors.forename: Kerry O
authors.initials: KO
authors.lastname: Cresawn
authors.forename: Lara R
authors.initials: LR
authors.lastname: Deruisseau
authors.forename: Sean
authors.initials: S
authors.lastname: Germain
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Lewis
authors.forename: Denise A
authors.initials: DA
authors.lastname: Cloutier
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004594:Electrophysiology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006003:Glycogen / Q000378:metabolism; D006009:Glycogen Storage Disease Type II / Q000201:enzymology / Q000235:genetics* / Q000628:therapy; D006321:Heart / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism; D009929:Organ Size; D010641:Phenotype; D019076:Transgenes / Q000235:genetics*; D000520:alpha-Glucosidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D006003:Glycogen; D000520:alpha-Glucosidases