Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
Systemic Delivery of scAAV8-Encoded MiR-29a Ameliorates Hepatic Fibrosis in Carbon Tetrachloride-Treated Mice.
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DOI：
10.1371/journal.pone.0124411
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Warren DS
中科院分区：
文献类型：
--
作者：
Knabel MK;Ramachandran K;Karhadkar S;Hwang HW;Creamer TJ;Chivukula RR;Sheikh F;Clark KR;Torbenson M;Montgomery RA;Cameron AM;Mendell JT;Warren DS
纤维化是指过量的细胞外基质(ECM)成分的积聚，是许多慢性炎症性疾病的关键特征。不幸的是，目前还没有专门针对这一重要致病机制的治疗方法。MicroRNAs(MiRNAs)是一种短的、非编码的RNA，它在转录后抑制靶基因的表达，基于miRNA的治疗方法的开发正在积极地应用于各种疾病。由于单个miRNA可以靶向多个基因，通常在同一途径内，单个miRNAs水平的变化可以潜在地影响疾病表型。MiR-29家族成员包括miR-29a、miR-29b和miR-29c，是ECM合成的强烈抑制因子，已有多个器官报道与纤维化相关的miR-29减少。我们观察到在四氯化碳(CCl_4)处理的肝纤维化小鼠以及暴露于促肝纤维化细胞因子转化生长因子-β的分离的人肝细胞中miR-29a/b/c的下调。重要的是，我们证明，尽管持续暴露在CCl4中，一次全身注射表达miR-29a的腺相关病毒(AAV)可以预防甚至逆转纤维化的组织学和生化证据。观察到的疗效与肝细胞的AAV转导有关，而不是与肝星状细胞有关，后者是纤维增生性肝病中主要的细胞外基质产生细胞。因此，我们的数据表明，使用临床相关的基因输送平台将miR-29输送到肝实质可以保护受损的肝脏免受纤维化的影响，并且考虑到miR-29与纤维化相关的持续下调，表明基于AAV-miR-29的治疗可能在治疗各种纤维增生性疾病方面有效。
Fibrosis refers to the accumulation of excess extracellular matrix (ECM) components and represents a key feature of many chronic inflammatory diseases. Unfortunately, no currently available treatments specifically target this important pathogenic mechanism. MicroRNAs (miRNAs) are short, non-coding RNAs that post-transcriptionally repress target gene expression and the development of miRNA-based therapeutics is being actively pursued for a diverse array of diseases. Because a single miRNA can target multiple genes, often within the same pathway, variations in the level of individual miRNAs can potently influence disease phenotypes. Members of the miR-29 family, which include miR-29a, miR-29b and miR-29c, are strong inhibitors of ECM synthesis and fibrosis-associated decreases in miR-29 have been reported in multiple organs. We observed downregulation of miR-29a/b/c in fibrotic livers of carbon tetrachloride (CCl4) treated mice as well as in isolated human hepatocytes exposed to the pro-fibrotic cytokine TGF-β. Importantly, we demonstrate that a single systemic injection of a miR-29a expressing adeno-associated virus (AAV) can prevent and even reverse histologic and biochemical evidence of fibrosis despite continued exposure to CCl4. The observed therapeutic benefits were associated with AAV transduction of hepatocytes but not hepatic stellate cells, which are the main ECM producing cells in fibroproliferative liver diseases. Our data therefore demonstrate that delivery of miR-29 to the hepatic parenchyma using a clinically relevant gene delivery platform protects injured livers against fibrosis and, given the consistent fibrosis-associated downregulation of miR-29, suggests AAV-miR-29 based therapies may be effective in treating a variety of fibroproliferative disorders.
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影响因子：
11.2
作者：
Katakowski M;Buller B;Wang X;Rogers T;Chopp M
通讯作者：
Chopp M
影响因子：
11.2
作者：
Lim, Philip K.;Bliss, Sarah A.;Rameshwar, Pranela
通讯作者：
Rameshwar, Pranela
DOI：
10.1165/rcmb.2010-0323oc
发表时间：
2011-08-01
影响因子：
6.4
作者：
Cushing, Leah;Kuang, Ping Ping;Lue, Jining
通讯作者：
Lue, Jining
影响因子：
4.4
作者：
Luna, Coralia;Li, Guorong;Gonzalez, Pedro
通讯作者：
Gonzalez, Pedro
影响因子：
13.5
作者：
Roderburg, Christoph;Urban, Gerd-Willem;Luedde, Tom
通讯作者：
Luedde, Tom