45. Adenoviral Gene Transfer of SERCA2a Restores Mechanical and Energetic Left-Ventricular Function in Spontaneously Diabetic Rats

CARDIAC GENE TRANSFER preference within cardiac tissue. 2 murine models for cardiac dysfunction; the alpha-sarcoglycan (asg -/-) knockout model for Limb Girdle Muscular Dystrophy Type 2D (LGMD-2D) and the acidalpha glucosidase (gaa-/-) knockout model for Pompe Disease are currently being characterized functionally and morphologically using both non-invasive MRI and histological techniques. LGMD-2D is the result of mutations in the alpha sarcoglycan (ASG) gene. This model displays the development of dystrophic lesions in cardiac and skeletal muscle. We have developed a non-invasive assay using MRI that enables us to locate and measure the random development of lesions within the muscles of asg -/- mice. We have demonstrated functional correction and prevention of disease progression in skeletal muscles injected with AAV-ASG. Studies are currently underway to demonstrate the same effect in cardiac tissue. The cells of the gaa-/ mouse contain lysosomes enlarged with glycogen due to a GAA enzyme deficiency. Previously, our lab has demonstrated that delivery of the human GAA gene to the skeletal muscle of this model is therapeutically beneficial. To evaluate gene delivery to the cardiac tissue of this model we are currently characterizing the cardiac phenotype of disease and assessing our ability to prevent disease presentation following optimized delivery of the human GAA gene. In conclusion, our maker-gene study has established that iv delivery using AAV9 is the most clinically advantageous combination of AAV serotype and delivery route for the transduction of cardiac tissue in vivo. We are now in the process of using this delivery method to demonstrate disease correction in two mouse models of cardiomyopathy.

ESPmax was increased over 200 mmHg and the EDPmax was decreased to 7 mmHg, although the ESPmax in Ad.βgal and saline groups was as low as that of OLETF. On the other hand, there was no difference in the slope and VO2 intercept of VO2 -PVA relation or in the minute VO2 for basal metabolism among all groups. Finally, the oxygen cost of LV contractility in response to calcium ion in OLETF hearts was about 3 times as high as that of LETO hearts (p