Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 501-507 |
| Number of pages | 7 |
| Journal | Molecular Therapy |
| Volume | 15 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2007 |
| Externally published | Yes |
Bibliographical note
Funding Information:We acknowledge the University of Florida Powell Gene Therapy Center Vector Core Laboratory, which produced the rAAV vectors used in this study. This work was supported by grants from the National Institutes of Health (NHLBI P01 HL59412-06, NIDDK P01 DK58327-03) and the American Heart Association, Florida and Puerto Rico Affiliate (KOC, CAP) and National Center (CM). BJB, The Johns Hopkins University, and the University of Florida could be entitled to patent royalties for inventions described in this paper.
