Abstract
Background: Interleukin-10 (IL-10) has proved to be important in recovery after acute myocardial infarction; increasing its expression in infarcted or bystander tissue therefore could be of great importance. Hydrodynamic DNA injection has been found to be very efficient in transferring genes to the liver of small animals, but the procedure is very aggressive and must be made compatible with clinical practice in a milder but not less efficient way. The present work evaluates the efficiency of noninvasive catheterization of the coronary sinus for human IL-10 gene transfer to infarcted and non-infarcted pig heart, with therapeutic production of the human protein. Methods: Myocardial infarction was induced in pigs by a catheter-based approach to occlude the left anterior descending artery. After myocardial infarction verification, two catheters were placed in the coronary sinus, one of them to block blood circulation and the other to retrogradely inject 50 ml of a saline solution of DNA (20 μg/ml) containing the hIL-10 gene, and testing different flow rate conditions (control, 2, 5 and 10 ml/s). Results: Therapeutic levels of hIL-10 protein were found in coronary sinus blood 2 and 72 hours after cathetermediated hydrofection at 5 and 10 ml/s flow rate. Molecular analyses to evaluate the delivered DNA, its transcription to RNA and translation were also performed, and data were expressed as copies per cell. Conclusion: Catheter-mediated gene transfer through the coronary sinus is a mild and well-tolerated procedure that achieves protective hIL-10 protein levels, which could minimize the inflammatory response after myocardial infarction.
Highlights
Several clinical trials with limited but encouraging results suggest that cardiac gene therapy is a promising therapeutic strategy for heart diseases such as ischemic events and heart failure [1,2,3,4,5,6,7]
The results show catheter‐ mediated retrograde injection of naked DNA bearing hIL‐10 gene in the pig coronary sinus vein to result in whole cardiac gene delivery and efficient protein expression in plasma
We confirmed that the contrast persisted as long as the balloon remained inflated, and the contrast mark observed confirmed that the whole coronary sinus was full of solution, since the contrast flowed out to the azygos vein, which is known to lead to the coronary sinus in pigs
Summary
Several clinical trials with limited but encouraging results suggest that cardiac gene therapy is a promising therapeutic strategy for heart diseases such as ischemic events and heart failure [1,2,3,4,5,6,7]. The classical lesser efficiency of non-viral procedures has been overcome by hydrodynamic gene transfer to mouse liver employing naked DNA, which has been shown to be an efficient and safe procedure in gene therapy [10,11,12] This procedure involves the rapid injection of a large volume (2 ml) of solution containing the gene of interest through the tail vein. The promising results obtained with this procedure suggest that similar or even better results could be achieved in cardiac tissue, since it is a smaller organ with a muscular structure that could offer more resistance to injection‐ induced distension This procedure was successfully transferred to the pig heart) through catheter‐mediated retrograde injection into the coronary sinus of 50 ml of a DNA solution containing the eGFP gene [19]. The present work evaluates the efficiency of noninvasive catheterization of the coronary sinus for human IL‐10 gene transfer to infarcted and non‐infarcted pig heart, with therapeutic production of the human protein
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