| Title: |
AAV delivery strategy with mechanical support for safe and efficacious cardiac gene transfer in swine. |
| Authors: |
Mazurek, Renata, Tharakan, Serena, Mavropoulos, Spyros A., Singleton, Deanndria T., Bikou, Olympia, Sakata, Tomoki, Kariya, Taro, Yamada, Kelly, Kohlbrenner, Erik, Liang, Lifan, Ravichandran, Anjali J., Watanabe, Shin, Hajjar, Roger J., Ishikawa, Kiyotake |
| Source: |
Nature Communications; 12/1/2024, Vol. 15 Issue 1, p1-12, 12p |
| Subject Terms: |
CORONARY occlusion, YORKSHIRE swine, ARTIFICIAL blood circulation, GENE expression, HEART failure |
| Abstract: |
Adeno-associated virus-based gene therapy is a promising avenue in heart failure treatment, but has shown limited cardiac virus uptake in humans, requiring new approaches for clinical translation. Using a Yorkshire swine ischemic heart failure model, we demonstrate significant improvement in gene uptake with temporary coronary occlusions assisted by mechanical circulatory support. We first show that mechanical support during coronary artery occlusions prevents hemodynamic deterioration (n = 5 female). Subsequent experiments show that coronary artery occlusions during gene delivery improve gene transduction, while adding coronary sinus occlusion (Stop-flow) further improves gene expression up to >1 million-fold relative to conventional intracoronary infusion. Complete survival during and after delivery (n = 10 female, n = 10 male) further indicates safety of the approach. Improved cardiac gene expression correlates with virus uptake without an increase in extra-cardiac expression. Stop-flow delivery of virus-sized gold nanoparticles exhibits enhanced endothelial adherence and uptake, suggesting a mechanism independent of virus biology. Together, utilizing mechanical support for cardiac gene delivery offers a clinically-applicable strategy for heart failure-targeted therapies. Efficient AAV gene delivery to the heart remains a challenge and hinders clinical translation. Here, coronary Stop-flow delivery with mechanical circulatory support dramatically improved gene expression while securing safety in a swine heart failure model. [ABSTRACT FROM AUTHOR] |
|
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |
