Safety and efficacy of high-dose adeno-associated virus 9 encoding sarcoplasmic reticulum Ca(2+) adenosine triphosphatase delivered by molecular cardiac surgery with recirculating delivery in ovine ischemic cardiomyopathy.

Abstract

Therapeutic safety and efficacy are the basic prerequisites for clinical gene therapy. We investigated the effect of high-dose molecular cardiac surgery with recirculating delivery (MCARD)-mediated adeno-associated virus 9 (AAV9)/sarcoplasmic reticulum Ca(2+) adenosine triphosphatase (SERCA2a) gene delivery on clinical parameters, oxidative stress, humoral and cellular immune responses, and cardiac remodeling. Ischemic cardiomyopathy was generated in a sheep model. The sheep were assigned to 1 of 2 groups: control (n = 10) and study (MCARD, n = 6). The control group underwent no intervention and the study group received 10(14) genome copies of AAV9/SERCA2a 4 weeks after infarction. Our ischemic model produced reliable infarcts leading to heart failure. The baseline ejection fraction in the MCARD group was 57.6% ± 1.6% versus 61.2% ± 1.9% in the control group (P > .05). At 12 weeks after infarction, the MCARD group had superior left ventricular function compared with the control group: stroke volume index, 46.6 ± 1.8 versus 35.8 ± 2.5 mL/m(2) (P < .05); ejection fraction, 46.2% ± 1.9% versus 38.7% ± 2.5% (P < .05); and left ventricular end-systolic and end-diastolic dimensions, 41.3 ± 1.7 versus 48.2 ± 1.4 mm and 51.2 ± 1.5 versus 57.6 ± 1.7 mm, respectively (P < .05). The markers of oxidative stress were significantly reduced in the infarct zone in the MCARD group. No positive T-cell-mediated immune response was seen in the MCARD group at any point. Myocyte hypertrophy was also significantly attenuated in the MCARD group compared with the control group. Cardiac overexpression of the SERCA2a gene by way of MCARD is a safe therapeutic intervention. It significantly improves left ventricular function, decreases markers of oxidative stress, abrogates myocyte hypertrophy, arrests remodeling, and does not induce a T-cell-mediated immune response.