Long-term preservation of cardiac structure and function after adeno-associated virus serotype 9-mediated microdystrophin gene transfer in mdx mice.
Long-term preservation of cardiac structure and function after adeno-associated virus serotype 9-mediated microdystrophin gene transfer in mdx mice.
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mdx 小鼠腺相关病毒血清型 9 介导的微肌营养不良蛋白基因转移后心脏结构和功能的长期保存。
DOI：
10.1089/hum.2011.017
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发表时间：
2012
影响因子：
4.2
通讯作者：
O. Müller
中科院分区：
文献类型：
--
作者：
S. Schinkel;R. Bauer;R. Bekeredjian;R. Stucka;D. Rutschow;Hanns Lochmüller;J. Kleinschmidt;H. Katus;O. Müller
肌营养不良蛋白在肌肉收缩中起着重要作用，它将细胞内的细胞骨架与细胞外的基质联系起来。营养不良蛋白基因突变导致蛋白质完全丧失，导致杜氏肌营养不良症(DMD)，通常与严重心肌病有关。使用基因转移到骨骼肌的DMD的早期临床试验正在进行中，但到营养不良的心肌的基因转移还没有在人类身上进行测试。本研究的目的是建立一种优化的心脏基因治疗方案，利用心脏启动子表达微营养不良蛋白(μDys)，并将其包装到腺相关病毒血清9型载体(AAV9AAV9)中。在这项研究中，成年mdx小鼠静脉注射1×10(12)个携带编码μDys基因的AAV9载体的基因组颗粒，该载体由普遍存在的巨细胞病毒启动子或心脏特异的巨细胞病毒增强型肌球蛋白轻链(MLC0.26)启动子控制。10个月后，两个AAV9载体都能在心肌中持续表达μDys，但MLC启动子提供的蛋白质水平大约高出4倍。通过组织病理学、超声心动图和左心室导管术评估，AAV9-CMV-MLC0.26-μDys对心脏形态和功能有显著的保护作用。综上所述，我们建立了一种AAV9介导的基因转移方法，在mdx小鼠的心脏中高效和特异地长期表达μ，从而产生持续的治疗效果。因此，这种方法可能是进一步转化为DMD相关心肌病的治疗策略的基础。
Dystrophin plays an important role in muscle contraction, linking the intracellular cytoskeleton to the extracellular matrix. Mutations of the dystrophin gene leading to a complete loss of the protein cause Duchenne muscular dystrophy (DMD), frequently associated with severe cardiomyopathy. Early clinical trials in DMD using gene transfer to skeletal muscle are underway, but gene transfer to dystrophic cardiac muscle has not yet been tested in humans. The aim of this study was to develop an optimized protocol for cardiac gene therapy in the mouse model of dystrophin deficiency (mdx), using a cardiac promoter for expression of a microdystrophin (μDys) transgene packaged into an adeno-associated virus serotype 9 vector (AAV9). In this study adult mdx mice were intravenously injected with 1×10(12) genomic particles of AAV9 vectors carrying a cDNA encoding μDys under the control of either a ubiquitously active cytomegalovirus (CMV) promoter or a cardiac-specific CMV-enhanced myosin light chain (MLC0.26) promoter. After 10 months, both AAV9 vectors led to sustained μDys expression in cardiac muscle, but the MLC promoter conferred about 4-fold higher protein levels. AAV9-CMV-MLC0.26-μDys resulted in significant protection of cardiac morphology and function as assessed by histopathology, echocardiography, and left ventricular catheterization. In conclusion, we established an AAV9-mediated gene transfer approach for efficient and specific long-term μDys expression in the hearts of mdx mice, resulting in a sustained therapeutic effect. Thus, this approach might be a basis for further translation into a treatment strategy for DMD-associated cardiomyopathy.
DOI：
10.1056/nejmoa1000228
发表时间：
2010-10-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Mendell JR;Campbell K;Rodino-Klapac L;Sahenk Z;Shilling C;Lewis S;Bowles D;Gray S;Li C;Galloway G;Malik V;Coley B;Clark KR;Li J;Xiao X;Samulski J;McPhee SW;Samulski RJ;Walker CM
通讯作者：
Walker CM
DOI：
10.1073/pnas.240335297
发表时间：
2000-12-05
影响因子：
11.1
作者：
Wang, B;Li, J;Xiao, X
通讯作者：
Xiao, X