Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model.
Cardiac AAV9-S100A1 gene therapy rescues post-ischemic heart failure in a preclinical large animal model.
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DOI：
10.1126/scitranslmed.3002097
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发表时间：
2011-07-20
影响因子：
17.1
通讯作者：
Most P
中科院分区：
文献类型：
--
作者：
Pleger ST;Shan C;Ksienzyk J;Bekeredjian R;Boekstegers P;Hinkel R;Schinkel S;Leuchs B;Ludwig J;Qiu G;Weber C;Raake P;Koch WJ;Katus HA;Müller OJ;Most P
作为临床应用的先决条件，我们在临床前大型动物心力衰竭模型中确定了腺相关病毒 (AAV) S100A1 基因疗法的长期治疗有效性和安全性。 S100A1 是心肌收缩力的正性肌力调节剂，在人类和各种动物模型的衰竭心肌细胞中被耗尽，心肌靶向 S100A1 基因转移通过恢复小动物模型中急性和慢性衰竭心脏的肌浆网钙 Ca2+ 处理来挽救心脏收缩功能。我们通过球囊阻塞左冠状动脉回旋支来诱发家猪心力衰竭，导致心肌梗塞。 2周后，当猪表现出明显的左心室收缩功能障碍时，我们通过逆行冠状静脉输送，将AAV9-S100A1给药至左心室非梗塞心肌。 AAV9-荧光素酶和盐水处理作为对照。第 14 周时，两个对照组均显示心肌 S100A1 蛋白表达显着下降，同时心脏功能和左心室重塑逐渐恶化。 AAV9-S100A1 治疗通过恢复心脏 S100A1 蛋白水平来预防和逆转这种表型。 S100A1 治疗可使心肌细胞 Ca2+ 循环、肌浆网钙处理和能量稳态正常化。转基因表达仅限于心脏组织，并且心脏外器官功能未受影响，这表明良好的安全性。这项转化研究显示了心脏 AAV9-S100A1 基因治疗在心力衰竭临床前模型中的临床前可行性、长期治疗效果和良好的安全性。我们的研究为 S100A1 基因治疗人类心力衰竭的临床试验提供了强有力的理由，这可能会补充当前治疗终末期心力衰竭的策略。
As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the pre-clinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure.
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影响因子：
4.8
作者：
Most, P;Remppis, A;Koch, WJ
通讯作者：
Koch, WJ
影响因子：
20.1
作者：
HOVEMADSEN, L;BERS, DM
通讯作者：
BERS, DM
影响因子：
1.5
作者：
Gusev, Konstantin;Ackermann, Gabriele E.;Niggli, Ernst
通讯作者：
Niggli, Ernst
DOI：
10.1016/0735-1097(93)90455-a
发表时间：
1993-10-01
影响因子：
24
作者：
HO, KKL;PINSKY, JL;LEVY, D
通讯作者：
LEVY, D
影响因子：
37.8
作者：
GREENBERG, B;QUINONES, MA;SHELTON, B
通讯作者：
SHELTON, B