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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII
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Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII

机译:新生儿辅助依赖性腺病毒载体基因治疗介导甲型血友病的纠正和对人因子VIII的耐受性

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摘要

Neonatal gene therapy is a promising strategy for treating a number of congenital diseases diagnosed shortly after birth as expression of therapeutic proteins during postnatal life may limit the pathologic consequences and result in a potential "cure." Hemophilia A is often complicated by the development of antibodies to recombinant protein resulting in treatment failure. Neonatal administration of vectors may avoid inhibitory antibody formation to factor VIII (FVIII) by taking advantage of immune immaturity. A helper-dependent adenoviral vector expressing human factor VIII was administered i.v. to neonatal hemophilia A knockout mice. Three days later, mice produced high levels of FVIII. Levels declined rapidly with animal growth to 5 wk of age with stable factor VIII expression thereafter to >1 y of age. Decline in factor VIII expression was not related to cell-mediated or humoral responses with lack of development of antibodies to capsid or human factor VIII proteins. Subsequent readministration and augmentation of expression was possible as operational tolerance was established to factor VIII without development of inhibitors; however, protective immunity to adenovirus remained.
机译:新生儿基因疗法是治疗出生后不久被诊断出的许多先天性疾病的有前途的策略,因为产后生命中治疗性蛋白的表达可能会限制病理结果并导致潜在的“治愈”。甲型血友病通常会因针对重组蛋白的抗体的开发而变得复杂,从而导致治疗失败。新生儿施用载体可通过利用免疫不成熟来避免针对因子VIII(FVIII)的抑制性抗体形成。静脉内施用表达人因子VIII的辅助依赖性腺病毒载体。新生儿血友病A基因敲除小鼠。三天后,小鼠产生了高水平的FVIII。随着动物的生长,其水平迅速下降至5周龄,其后稳定的VIII因子表达达到> 1周岁。缺乏针对衣壳或人凝血因子VIII的抗体的发展,凝血因子VIII的表达下降与细胞介导或体液反应无关。随后的重新给药和表达的增加是可能的,因为建立了对因子VIII的操作耐受性而没有抑制剂的发展。但是,仍保留对腺病毒的保护性免疫力。

著录项

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  • 作者单位

    Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;

    Department of Molecular and Human Genetics,Baylor College of Medicine, Houston, TX 77030;

    Department of Molecular and Human Genetics,Baylor College of Medicine, Houston, TX 77030;

    Department of Molecular and Human Genetics,Baylor College of Medicine, Houston, TX 77030,Howard Hughes Medical Institute, David Geffen School of Medicine,University of California, Los Angeles, CA 90095;

    Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, CA 90095,Department of Medicine, David Geffen School of Medicine,University of California, Los Angeles, CA 90095;

  • 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

    immune response; coagulation;

    机译:免疫反应;凝血;

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