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Investigation of fibrotic factors during the exon-skipping therapy using antisense oligonucleotide for muscular dystrophy

使用反义寡核苷酸治疗肌营养不良症的外显子跳跃疗法期间纤维化因素的研究

基本信息

批准号：
23591495
负责人：
TAKESHIMA Yasuhiro
金额：
$ 3.33万
依托单位：
Kobe University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2011
资助国家：
日本
起止时间：
2011 至 2013
项目状态：
已结题

项目摘要

To enhance the effectiveness of antisense oligonucleotide (AO)-mediated exon skipping therapy for Duchenne muscular dystrophy (DMD), the relationship of fibrosis and inflammation to DMD was examined. At the beginning pharmacodynamics of the AO inducing the skipping of exon 45(AO85) was examined using cell-free splicing system, and the EC50 of AO85 was revealed to be 58.0 nM. Then, urinary tetranor PGDM which is major urinary metabolite of prostaglandin (PG) D2 were shown to be increased in DMD patients and became higher with advancing age. It was indicated that PGD2-mediated inflammation plays a role in the pathology of DMD. Furthermore, administration of AO85 to DMD cases resulted in the improvement of some inflammatory cytokines. These results indicated that fibrosis and inflammation were involved in the pathogenesis of DMD, and the modification of these factors was considered as one possible strategy for the enhancement of the effectiveness of AO-mediated exon skipping therapy.

为了提高反义寡核苷酸（AO）介导的外显子跳跃治疗Duchenne型肌营养不良症（DMD）的有效性，研究了纤维化和炎症与DMD的关系。在开始时，使用无细胞剪接系统检查了AO诱导外显子45（AO 85）跳读的药效学，并且AO 85的EC 50显示为58.0 nM。尿中前列腺素D_2的主要代谢产物四氢吡喃PGDM在DMD患者中升高，并随年龄增长而升高。提示PGD2介导的炎症反应在DMD的病理过程中起一定作用。此外，对DMD病例施用AO85导致一些炎性细胞因子的改善。这些结果表明纤维化和炎症参与了DMD的发病机制，并且这些因素的修饰被认为是增强AO介导的外显子跳跃治疗的有效性的可能策略之一。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pathogenic orphan transduction created by a nonreference LINE-1 retrotransposon.

DOI：
10.1002/humu.21663
发表时间：
2012-02
期刊：
HUMAN MUTATION
影响因子：
3.9
作者：
Solyom, Szilvia;Ewing, Adam D.;Hancks, Dustin C.;Takeshima, Yasuhiro;Awano, Hiroyuki;Matsuo, Masafumi;Kazazian, Haig H., Jr.
通讯作者：
Kazazian, Haig H., Jr.

Utility of transmural myocardial strain profile for prediction of early left ventricular dysfunction in patients with Duchenne muscular dystrophy.

透壁心肌应变曲线在预测杜氏肌营养不良症患者早期左心室功能障碍中的应用。

DOI：
发表时间：
2013
期刊：
Am J Cardiol.
影响因子：
0
作者：
Yamamoto T;Tanaka H;Matsumoto K;Lee T;Awano H;Yagi M;Imanishi T;Hayashi N;Takeshima Y;Kawai H;Kawano S;Hirata K.
通讯作者：
Hirata K.

Three-dimensional gait analysis of Duchenne muscular dystrophy; a trial to evaluate the therapeutic effect of RNA/ENA chimera antisense oligonucleotide that induces dystrophin exon 45 skipping

杜氏肌营养不良症的三维步态分析；