title: Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice.
abstract: Pompe disease is an autosomal recessive genetic disorder characterized by a deficiency of the enzyme responsible for degradation of lysosomal glycogen (acid α-glucosidase (GAA)). Cardiac dysfunction and respiratory muscle weakness are primary features of this disorder. To attenuate the progressive and rapid accumulation of glycogen resulting in cardiorespiratory dysfunction, adult Gaa (-/-) mice were administered a single systemic injection of rAAV2/9-DES-hGAA (AAV9-DES) or bimonthly injections of recombinant human GAA (enzyme replacement therapy (ERT)). Assessment of cardiac function and morphology was measured 1 and 3 months after initiation of treatment while whole-body plethysmography and diaphragmatic contractile function was evaluated at 3 months post-treatment in all groups. Gaa (-/-) animals receiving either AAV9-DES or ERT demonstrated a significant improvement in cardiac function and diaphragmatic contractile function as compared to control animals. AAV9-DES treatment resulted in a significant reduction in cardiac dimension (end diastolic left ventricular mass/gram wet weight; EDMc) at 3 months postinjection. Neither AAV nor ERT therapy altered minute ventilation during quiet breathing (eupnea). However, breathing frequency and expiratory time were significantly improved in AAV9-DES animals. These results indicate systemic delivery of either strategy improves cardiac function but AAV9-DES alone improves respiratory parameters at 3 months post-treatment in a murine model of Pompe disease.
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Meghan S
authors.initials: MS
authors.lastname: Soustek
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Adrian Gary
authors.initials: AG
authors.lastname: Todd
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Mah
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Cloutier
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Kelley
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clement
authors.affiliation: Department of Physical Therapy, University of Florida , Gainesville, Florida, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
authors.affiliation: Department of Pediatrics, University of Florida , Gainesville, Florida, USA ; Powell Gene Therapy Center, University of Florida , Gainesville, Florida, USA.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne