410. Physiological Correction of Glycogen Storage Disease Type II Using Adeno-Associated Virus Serotype 1 Vectors

Abstract

Glycogen storage disease type II (GSDII) is caused by a lack of functional lysosomal acid |[alpha]|-glucosidase (GAA) and results in massive storage of glycogen in lysosomal compartments, ultimately leading to fatal severe hypertrophic cardiomyopathy and respiratory insufficiency. Previously, we demonstrated the ability of a single intravenous administration of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to restore therapeutic levels of cardiac and diaphragmatic GAA enzymatic activity with concomitant clearance of glycogen in vivo in a mouse model of GSDII (Gaa-/-). We have further characterized both cardiac and respiratory function in rAAV2/1-treated animals one year post-treatment. Similar to the GSDII patient population, electrocardiogram (ECG) measurements (P-R interval) are significantly shortened in the mouse model. In rAAV2/1-treated mice, we show a significant improvement in cardiac conductance with prolonged P-R intervals of 39.34 |[plusmn]| 1.6 ms, as compared to untreated controls (35.58 |[plusmn]| 0.57 ms) (p|[le]|0.05). In addition, using cardiac magnetic resonance imaging (MRI) we note a marked decrease in cardiac left ventricular mass from 181.99 |[plusmn]| 10.70 mg in untreated age-matched controls to 141.97 |[plusmn]| 19.15 mg in the rAAV2/1-treated mice. Furthermore the mice displayed increased diaphragmatic contractile force to approximately 90% of wild-type peak forces with corresponding significantly improved ventilation (particularly in frequency, minute ventilation, and peak inspiratory flow), as measured using barometric whole body plethysmography. 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.