Physiological correction of pompe disease by systemic delivery of adeno-associated virus serotype 1 vectors

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Molecular Therapy


Pompe disease is caused by a lack of functional lysosomal acid α-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.

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