Comparative impact of AAV and enzyme replacement therapy on respiratory and cardiac function in adult Pompe mice

• Main Authors: Darin J Falk, Meghan S Soustek, Adrian Gary Todd, Cathryn S Mah, Denise A Cloutier, Jeffry S Kelley, Nathalie Clement, David D Fuller, Barry J Byrne
• Format: Article
• Language: English
• Published: Elsevier 2015-01-01
• Series: Molecular Therapy: Methods & Clinical Development
• Online Access: http://www.sciencedirect.com/science/article/pii/S2329050116300195

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 Gaaâ/â 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. Gaaâ/â 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.