AAV delivery strategy with mechanical support for safe and efficacious cardiac gene transfer in swine

Renata Mazurek, Serena Tharakan, Spyros A. Mavropoulos, Deanndria T. Singleton, Olympia Bikou, Tomoki Sakata, Taro Kariya, Kelly Yamada, Erik Kohlbrenner, Lifan Liang, Anjali J. Ravichandran, Shin Watanabe, Roger J. Hajjar and Kiyotake Ishikawa ()
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Renata Mazurek: Icahn School of Medicine at Mount Sinai
Serena Tharakan: Icahn School of Medicine at Mount Sinai
Spyros A. Mavropoulos: Icahn School of Medicine at Mount Sinai
Deanndria T. Singleton: Icahn School of Medicine at Mount Sinai
Olympia Bikou: Icahn School of Medicine at Mount Sinai
Tomoki Sakata: Icahn School of Medicine at Mount Sinai
Taro Kariya: Icahn School of Medicine at Mount Sinai
Kelly Yamada: Icahn School of Medicine at Mount Sinai
Erik Kohlbrenner: Icahn School of Medicine at Mount Sinai
Lifan Liang: Icahn School of Medicine at Mount Sinai
Anjali J. Ravichandran: Icahn School of Medicine at Mount Sinai
Shin Watanabe: Icahn School of Medicine at Mount Sinai
Roger J. Hajjar: Icahn School of Medicine at Mount Sinai
Kiyotake Ishikawa: Icahn School of Medicine at Mount Sinai

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-54635-x

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