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

doi:10.1038/mt.2014.127

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 language	English (US)
Pages (from-to)	2038-2045
Number of pages	8
Journal	Molecular Therapy
Volume	22
Issue number	12
DOIs	https://doi.org/10.1038/mt.2014.127
State	Published - Dec 11 2014

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1038/mt.2014.127

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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

Ishikawa, K, Fish, KM, Tilemann, L, Rapti, K, Aguero, J, Santos-Gallego, CG, Lee, A, Karakikes, I, Xie, C, Akar, FG, Shimada, YJ, Gwathmey, JK, Asokan, A, McPhee, S, Samulski, J, Samulski, RJ, Sigg, DC, Weber, T, Kranias, EG & Hajjar, RJ 2014, 'Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure', Molecular Therapy, vol. 22, no. 12, pp. 2038-2045. https://doi.org/10.1038/mt.2014.127

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

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.",

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

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doi = "10.1038/mt.2014.127",

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AU - Fish, Kenneth M.

AU - Tilemann, Lisa

AU - Rapti, Kleopatra

AU - Aguero, Jaume

AU - Santos-Gallego, Carlos G.

AU - Lee, Ahyoung

AU - Karakikes, Ioannis

AU - Xie, Chaoqin

AU - Akar, Fadi G.

AU - Shimada, Yuichi J.

AU - Gwathmey, Judith K.

AU - Asokan, Aravind

AU - McPhee, Scott

AU - Samulski, Jade

AU - Samulski, Richard Jude

AU - Sigg, Daniel C.

AU - Weber, Thomas

AU - Kranias, Evangelia G.

AU - Hajjar, Roger J.

PY - 2014/12/11

Y1 - 2014/12/11

N2 - 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.

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

Abstract

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