Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure

Kiyotake Ishikawa, Kenneth M. Fish, Lisa Tilemann, Kleopatra Rapti, Jaume Aguero, Carlos G. Santos-Gallego, Ahyoung Lee, Ioannis Karakikes, Chaoqin Xie, Fadi G. Akar, Yuichi J. Shimada, Judith K. Gwathmey, Aravind Asokan, Scott McPhee, Jade Samulski, Richard Jude Samulski, Daniel C. Sigg, Thomas Weber, Evangelia G. Kranias, Roger J. Hajjar

Research output: Contribution to journalArticle

Abstract

Cardiac gene therapy has emerged as a promising option to treat advanced heart failure (HF). Advances in molecular biology and gene targeting approaches are offering further novel options for genetic manipulation of the cardiovascular system. The aim of this study was to improve cardiac function in chronic HF by overexpressing constitutively active inhibitor-1 (I-1c) using a novel cardiotropic vector generated by capsid reengineering of adeno-associated virus (BNP116). One month after a large anterior myocardial infarction, 20 Yorkshire pigs randomly received intracoronary injection of either high-dose BNP116.I-1c (1.0 × 10 13 vector genomes (vg), n = 7), low-dose BNP116.I-1c (3.0 × 10 12 vg, n = 7), or saline (n = 6). Compared to baseline, mean left ventricular ejection fraction increased by 5.7% in the high-dose group, and by 5.2% in the low-dose group, whereas it decreased by 7% in the saline group. Additionally, preload-recruitable stroke work obtained from pressure-volume analysis demonstrated significantly higher cardiac performance in the high-dose group. Likewise, other hemodynamic parameters, including stroke volume and contractility index indicated improved cardiac function after the I-1c gene transfer. Furthermore, BNP116 showed a favorable gene expression pattern for targeting the heart. In summary, I-1c overexpression using BNP116 improves cardiac function in a clinically relevant model of ischemic HF.

Original languageEnglish (US)
Pages (from-to)2038-2045
Number of pages8
JournalMolecular Therapy
Volume22
Issue number12
DOIs
StatePublished - Dec 11 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Ishikawa, K., Fish, K. M., Tilemann, L., Rapti, K., Aguero, J., Santos-Gallego, C. G., Lee, A., Karakikes, I., Xie, C., Akar, F. G., Shimada, Y. J., Gwathmey, J. K., Asokan, A., McPhee, S., Samulski, J., Samulski, R. J., Sigg, D. C., Weber, T., Kranias, E. G., & Hajjar, R. J. (2014). Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Molecular Therapy, 22(12), 2038-2045. https://doi.org/10.1038/mt.2014.127