Protein Phosphatase Inhibitor-1 Gene Therapy in a Swine Model of Nonischemic Heart Failure

Shin Watanabe, Kiyotake Ishikawa, Kenneth Fish, Jae Gyun Oh, Lukas J. Motloch, Erik Kohlbrenner, Philyoung Lee, Chaoqin Xie, Ahyoung Lee, Lifan Liang, Changwon Kho, Lauren Leonardson, Maritza McIntyre, Scott Wilson, R. Jude Samulski, Evangelia G. Kranias, Thomas Weber, Fadi G. Akar, Roger J. Hajjar

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Background Increased protein phosphatase-1 in heart failure (HF) induces molecular changes deleterious to the cardiac cell. Inhibiting protein phosphatase-1 through the overexpression of a constitutively active inhibitor-1 (I-1c) has been shown to reverse cardiac dysfunction in a model of ischemic HF. Objectives This study sought to determine the therapeutic efficacy of a re-engineered adenoassociated viral vector carrying I-1c (BNP116.I-1c) in a preclinical model of nonischemic HF, and to assess thoroughly the safety of BNP116.I-1c gene therapy. Methods Volume-overload HF was created in Yorkshire swine by inducing severe mitral regurgitation. One month after mitral regurgitation induction, pigs were randomized to intracoronary delivery of either BNP116.I-1c (n = 6) or saline (n = 7). Therapeutic efficacy and safety were evaluated 2 months after gene delivery. Additionally, 24 naive pigs received different doses of BNP116.I-1c for safety evaluation. Results At 1 month after mitral regurgitation induction, pigs developed HF as evidenced by increased left ventricular end-diastolic pressure and left ventricular volume indexes. Treatment with BNP116.I-1c resulted in improved left ventricular ejection fraction (−5.9 ± 4.2% vs. 5.5 ± 4.0%; p < 0.001) and adjusted dP/dt maximum (−3.39 ± 2.44 s-1 vs. 1.30 ± 2.39 s-1; p = 0.007). Moreover, BNP116.I-1c-treated pigs also exhibited a significant increase in left atrial ejection fraction at 2 months after gene delivery (−4.3 ± 3.1% vs. 7.5 ± 3.1%; p = 0.02). In vitro I-1c gene transfer in isolated left atrial myocytes from both pigs and rats increased calcium transient amplitude, consistent with its positive impact on left atrial contraction. We found no evidence of adverse electrical remodeling, arrhythmogenicity, activation of a cellular immune response, or off-target organ damage by BNP116.I-1c gene therapy in pigs. Conclusions Intracoronary delivery of BNP116.I-1c was safe and improved contractility of the left ventricle and atrium in a large animal model of nonischemic HF.

Original languageEnglish
Pages (from-to)1744-1756
Number of pages13
JournalJournal of the American College of Cardiology
Volume70
Issue number14
DOIs
StatePublished - 3 Oct 2017

Keywords

  • chimeric adenoassociated virus
  • contractility
  • inhibitor-1
  • intracoronary gene therapy
  • mitral regurgitation

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