Watanabe Shin, Ishikawa Kiyotake, Fish Kenneth, Oh Jae Gyun, Motloch Lukas J, Kohlbrenner Erik, Lee Philyoung, Xie Chaoqin, Lee Ahyoung, Liang Lifan, Kho Changwon, Leonardson Lauren, McIntyre Maritza, Wilson Scott, Samulski R Jude, Kranias Evangelia G, Weber Thomas, Akar Fadi G, Hajjar Roger J
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
ASKBIO, Chapel Hill, North Carolina.
J Am Coll Cardiol. 2017 Oct 3;70(14):1744-1756. doi: 10.1016/j.jacc.2017.08.013.
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.
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.
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.
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 vs. 1.30 ± 2.39 s; 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.
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.
心力衰竭（HF）中蛋白磷酸酶 -1增加会诱导对心肌细胞有害的分子变化。通过组成型活性抑制剂 -1（I-1c）的过表达抑制蛋白磷酸酶 -1已被证明可在缺血性HF模型中逆转心脏功能障碍。
本研究旨在确定携带I-1c的重组腺相关病毒载体（BNP116.I-1c）在非缺血性HF临床前模型中的治疗效果，并全面评估BNP116.I-1c基因治疗的安全性。
通过诱导严重二尖瓣反流在约克郡猪中建立容量超负荷HF模型。二尖瓣反流诱导1个月后，将猪随机分为冠状动脉内注射BNP116.I-1c组（n = 6）或生理盐水组（n = 7）。基因递送2个月后评估治疗效果和安全性。此外，24只未处理的猪接受不同剂量的BNP116.I-1c进行安全性评估。
二尖瓣反流诱导1个月后，猪出现HF，表现为左心室舒张末期压力和左心室容积指数增加。BNP116.I-1c治疗导致左心室射血分数改善（-5.9±4.2%对5.5±4.0%；p<0.001）和调整后的最大dP/dt改善（-3.39±2.44秒对1.30±2.39秒；p = 0.007）。此外，基因递送2个月后，接受BNP116.I-1c治疗的猪左心房射血分数也显著增加（-4.3±3.1%对7.5±3.1%；p = 0.02）。在来自猪和大鼠的分离左心房心肌细胞中进行的体外I-1c基因转移增加了钙瞬变幅度，与其对左心房收缩的积极影响一致。我们没有发现BNP116.I-1c基因治疗在猪中引起不良电重构、致心律失常性、细胞免疫反应激活或脱靶器官损伤的证据。
在非缺血性HF的大型动物模型中，冠状动脉内递送BNP116.I-1c是安全的，并改善了左心室和左心房的收缩性。
