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Mol Ther: 常染色体隐性视网膜色素变性获得突破

  1. AAV
  2. 基因治疗
  3. 常染色体隐性视网膜色素变性

来源:生物谷 2015-03-26 11:14

在病人来源的MFRP缺陷的ips-RPE中通过AAV(Y733F)载体表达人MFRP能够逆转肌动蛋白重组紊乱和恢复顶绒毛状突起物。AAV-处理的MFRP突变的ips-RPE恢复了色素沉着和表皮防御。

 2014年6月6日讯/生物谷BIOON/-膜卷曲相关蛋白(MFRP)的缺陷导致常染色体隐性视网膜色素变性。而MFRP编码了视网膜色素上皮细胞未知功能的膜受体。

 
在人诱导多能干细胞(ips)来源的RPE中,MFRP的精确的表达水平和MFRP的双顺反子CTRP5对于肌动蛋白的组织至关重要。当在正常的RPE细胞中过表达CTRP5表现出相似于MFRP缺陷病人来源的RPE(ips-RPE)。在病人来源的MFRP缺陷的ips-RPE中通过AAV(Y733F)载体表达人MFRP能够逆转肌动蛋白重组紊乱和恢复顶绒毛状突起物。AAV-处理的MFRP突变的ips-RPE恢复了色素沉着和表皮防御。AAV-介导的基因治疗在Mfrprd6/Mfrprd6 鼠-一种公认的RP临床前动物模型中进行有效性评估,在AAV-Mfrp治疗鼠中视觉功能得到了长期的提高。
 
这项研究是ips-RPE细胞成功用于基因治疗受体的首次报道,在病人来源的细胞系和 Mfrprd6/Mfrprd6小鼠模型中可见的有益应答表明:
这种由MERP突变引起的退化可以作为介入治疗的潜在靶标。(生物谷Bioon.com)
 
 
Gene therapy in patient-specific stem cell lines and mice with membrane frizzled-related protein (MFRP) defects.
 
Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in na?ve human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrprd6/Mfrprd6 mice-an established preclinical model of RP-and long-term improvement in visual function was observed in AAV-Mfrp treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines and the Mfrprd6/Mfrprd6 preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials.

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