Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction.
Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction.
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DOI：
10.1126/scitranslmed.abd6892
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发表时间：
2021-06-30
影响因子：
17.1
通讯作者：
中科院分区：
文献类型：
--
作者：
人类心力衰竭是全世界死亡的主要原因，是细胞更新不良可能导致的慢性疾病的一个突出例子。 Hippo 信号通路是一种抑制性激酶级联，可抑制转基因小鼠心肌梗塞后成年心肌细胞（心肌细胞）的增殖和更新。在这里，我们研究了一种基于腺相关病毒 9 (AAV9) 的基因疗法，在缺血/再灌注诱发的心肌梗死猪模型中局部敲除边界区心肌细胞中的 Hippo 通路基因 Salvador (Sav)。心肌梗死两周后，当猪出现左心室收缩功能障碍时，我们通过导管介导的心内膜下注射将 AAV9-Sav 短发夹 RNA (shRNA) 或携带绿色荧光蛋白 (GFP) 的对照 AAV9 病毒载体直接注入边界区心肌细胞。注射三个月后，与接受 AAV9-GFP 的猪相比，接受高剂量 AAV9-Sav-shRNA 治疗的猪心脏的射血分数（左心室收缩功能的衡量标准）提高了 14.3%，心肌细胞分裂的证据，并且疤痕尺寸减小。 AAV9-Sav-shRNA 处理的猪心脏还表现出毛细血管密度增加和心肌细胞倍性减少。 AAV9-Sav-shRNA 基因治疗耐受性良好，不会导致死亡。此外，肝脏和肺部病理学显示没有肿瘤形成。心肌梗死后，将 AAV9-Sav-shRNA 基因治疗局部递送至猪心脏的边缘区心肌细胞，可导致组织更新和功能改善，可能有助于治疗心力衰竭。
Human heart failure, a leading cause of death worldwide, is a prominent example of a chronic disease that may result from poor cell renewal. The Hippo signaling pathway is an inhibitory kinase cascade that represses adult heart muscle cell (cardiomyocyte) proliferation and renewal after myocardial infarction in genetically modified mice. Here, we investigated an adeno-associated virus 9 (AAV9)–based gene therapy to locally knock down the Hippo pathway gene Salvador (Sav) in border zone cardiomyocytes in a pig model of ischemia/reperfusion-induced myocardial infarction. Two weeks after myocardial infarction, when pigs had left ventricular systolic dysfunction, we administered AAV9-Sav–short hairpin RNA (shRNA) or a control AAV9 viral vector carrying green fluorescent protein (GFP) directly into border zone cardiomyocytes via catheter-mediated subendocardial injection. Three months after injection, pig hearts treated with a high dose of AAV9-Sav-shRNA exhibited a 14.3% improvement in ejection fraction (a measure of left ventricular systolic function), evidence of cardiomyocyte division, and reduced scar sizes compared to pigs receiving AAV9-GFP. AAV9-Sav-shRNA–treated pig hearts also displayed increased capillary density and reduced cardiomyocyte ploidy. AAV9-Sav-shRNA gene therapy was well tolerated and did not induce mortality. In addition, liver and lung pathology revealed no tumor formation. Local delivery of AAV9-Sav-shRNA gene therapy to border zone cardiomyocytes in pig hearts after myocardial infarction resulted in tissue renewal and improved function and may have utility in treating heart failure.
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影响因子：
4.6
作者：
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通讯作者：
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DOI：
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DOI：
10.1073/pnas.2000175117
发表时间：
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影响因子：
11.1
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通讯作者：
Segil, Neil