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Mol Ther. 2014 Dec;22(12):2038-45. doi: 10.1038/mt.2014.127. Epub 2014 Jul 15.

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

Author information

1
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
2
Department of Medicine, Beth Israel Medical Center, University Hospital and Manhattan Campus for the Albert Einstein College of Medicine, New York, New York, USA.
3
Gwathmey Inc., Cambridge, Massachusetts, USA.
4
Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, USA.
5
Asklepios BioPharmaceutical, Chapel Hill, NC.
6
Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, Minnesota, USA.
7
Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio, USA.

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.

PMID:
25023328
PMCID:
PMC4429688
DOI:
10.1038/mt.2014.127
[Indexed for MEDLINE]
Free PMC Article

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