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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Design of embedded chimeric peptide nucleic acids that efficiently enter and accurately reactivate gene expression in vivo
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Design of embedded chimeric peptide nucleic acids that efficiently enter and accurately reactivate gene expression in vivo

机译：嵌入式嵌合肽核酸的设计，可有效进入体内并准确地重新激活基因表达

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摘要

Pharmacological treatments designed to reactivate fetal Y-globin can lead to an effective and successful clinical outcome in patients with hemoglobinopathies. However, new approaches remain highly desired because such treatments are not equally effective for all patients, and toxicity issues remain. We have taken a systematic approach to develop an embedded chimeric peptide nucleic acid (PNA) that effectively enters the cell and the nucleus, binds to its target site at the human fetal Y-globin promoter, and reactivates this transcript in adult transgenic mouse bone marrow and human primary peripheral blood cells. In vitro and in vivo DNA-binding assays in conjunction with live-cell imaging have been used to establish and optimize chimeric PNA design parameters that lead to successful gene activation. Our final molecule contains a specific γ-promoter-binding PNA sequence embedded within two amino acid motifs: one leads to efficient celluclear entry, and the other generates transcriptional reactivation of the target. These embedded PNAs overcome previous limitations and are generally applicable to the design of in vivo transcriptional activation reagents that can be directed to any promoter region of interest and are of direct relevance to clinical applications that would benefit from such a need.
机译：旨在重新激活胎儿Y球蛋白的药理学治疗可以使血红蛋白病患者获得有效而成功的临床结果。然而，由于这种治疗方法并非对所有患者都同样有效，并且仍然存在毒性问题，因此仍然非常需要新的方法。我们已采取系统的方法来开发一种嵌入的嵌合肽核酸（PNA），该核酸可有效进入细胞和细胞核，结合至其在人类胎儿Y-球蛋白启动子上的靶位，并在成人转基因小鼠骨髓中重新激活该转录本和人类原发性外周血细胞。结合活细胞成像的体外和体内DNA结合测定已被用于建立和优化导致成功激活基因的嵌合PNA设计参数。我们的最终分子包含嵌入两个氨基酸基序中的特定的γ-启动子结合PNA序列：一个导致有效的细胞/核进入，另一个导致靶标的转录重新激活。这些嵌入的PNA克服了先前的局限性，通常适用于体内转录激活试剂的设计，该试剂可针对任何感兴趣的启动子区域，并且与将从此类需求中受益的临床应用直接相关。

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  • 作者

    Joy Chen; Kenneth R. Peterson; Camelia Iancu-Rubin; James J. Bicker;

  • 作者单位

    Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, 10029;

    rnDepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160;

    rnDepartment of Medicine, Mount Sinai School of Medicine, New York, NY, 10029 Tisch Cancer Institute,Mount Sinai School of Medicine, New York, NY, 10029;

    rnDepartment of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, 10029 Tisch Cancer Institute,Mount Sinai School of Medicine, New York, NY, 10029 Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY, 10029 Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, Box 1020, One Gustave L Levy Place, New York, NY 10029;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    γ-globin gene reactivation; primary human CD34+ cells;

    机译：γ-珠蛋白基因激活;人原代CD34 +细胞;

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