The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice
The artificial gene Jazz, a transcriptional regulator of utrophin, corrects the dystrophic pathology in mdx mice
复制标题
DOI：
10.1093/hmg/ddp539
复制
发表时间：
2010-03-01
影响因子：
3.5
通讯作者：
Passananti, Claudio
中科院分区：
文献类型：
--
作者：
Di Certo, Maria Grazia;Corbi, Nicoletta;Passananti, Claudio
细胞骨架蛋白肌营养不良蛋白的缺乏导致杜氏肌营养不良症（DMD）。utrophin蛋白是DMD患者中肌营养不良蛋白替代的最佳候选物。为了获得营养不良肌肉中utrophin表达的治疗水平，我们开发了一种基于使用人工锌指转录因子（ZF ATFs）的替代策略。ZF ATF 'Jazz'最近通过产生在肌肉水平特异性表达Jazz的转基因小鼠进行了体内工程和测试。为了验证ZF ATF技术用于DMD治疗，我们通过将Jazz转基因小鼠与肌营养不良蛋白缺陷型mdx小鼠杂交产生了第二种小鼠模型。在这里，我们表明，人工爵士蛋白恢复肌膜的完整性，并防止mdx小鼠的营养不良性疾病的发展。这种独特的动物模型建立了这样的概念，即使用ZF ATF技术可以有效地开发DMD的基于utrophin的疗法，并将Jazz作为DMD疗法的新型治疗分子。
The absence of the cytoskeletal protein dystrophin results in Duchenne muscular dystrophy (DMD). The utrophin protein is the best candidate for dystrophin replacement in DMD patients. To obtain therapeutic levels of utrophin expression in dystrophic muscle, we developed an alternative strategy based on the use of artificial zinc finger transcription factors (ZF ATFs). The ZF ATF 'Jazz' was recently engineered and tested in vivo by generating a transgenic mouse specifically expressing Jazz at the muscular level. To validate the ZF ATF technology for DMD treatment we generated a second mouse model by crossing Jazz-transgenic mice with dystrophin-deficient mdx mice. Here, we show that the artificial Jazz protein restores sarcolemmal integrity and prevents the development of the dystrophic disease in mdx mice. This exclusive animal model establishes the notion that utrophin-based therapy for DMD can be efficiently developed using ZF ATF technology and candidates Jazz as a novel therapeutic molecule for DMD therapy.