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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Imaging of enzyme replacement therapy using PET
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Imaging of enzyme replacement therapy using PET

机译：使用PET进行酶替代疗法的成像

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摘要

Direct enzyme replacement therapy (ERT) has been introduced as a means to treat a number of rare, complex genetic conditions associated with lysosomal dysfunction. Gaucher disease was the first for which this therapy was applied and remains the prototypical example. Although ERT using recombinant lysosomal enzymes has been shown to be effective in altering the clinical course of Gaucherdisease, Fabry disease, Hurler syndrome. Hunter syndrome, Maroteaux-Lamy syndrome, and Pompe disease, the recalcitrance of certain disease manifestations underscores important unanswered questions related to dosing regimes, tissue half-life of the recombinant enzyme and the ability of intravenously administered enzyme to reach critical sites of known disease pathology. We have developed an innovative method for tagging acid β-glucocerebrosi-dase (GCase), the recombinant enzyme formulated in Cerezyme? used to treat Gaucher disease, using an ~(18)F-labeled substrate analogue that becomes trapped within the active site of the enzyme. Using micro-PET we show that the tissue distribution of injected enzyme can be imaged in a murine model and that the PET data correlate with tissue ~(18)F counts. Further we show that PET imaging readily monitors pharmacokinetic changes effected by receptor blocking. The ability to ~(18)F-Iabel GCase to monitor the enzyme distribution and tissue half-life in vivo by PET provides a powerful research tool with an immediate clinical application to Gaucher disease and a clear path for application to other ERTs.
机译：直接酶替代疗法（ERT）已被引入作为治疗许多与溶酶体功能障碍相关的罕见，复杂遗传病的方法。高雪氏病是第一种应用这种疗法的疾病，至今仍是典型的例子。尽管已证明使用重组溶酶体酶的ERT在改变Gaucherdisease，Fabry病，Hurler综合征的临床过程中是有效的。亨特综合症，马洛-拉米综合症和庞贝病，某些疾病表现的顽固性突出了与给药方案，重组酶的组织半衰期以及静脉内施用的酶到达已知疾病病理关键部位的能力有关的重要未解决问题。我们已经开发出一种创新的方法来标记酸性β-葡萄糖脑苷脂酶（GCase），这是Cerezyme？中配制的重组酶。用来治疗高雪氏病，使用〜（18）F标记的底物类似物，该类似物被困在酶的活性位点内。使用微型PET，我们显示了可以在鼠模型中对注射的酶的组织分布进行成像，并且PET数据与组织〜（18）F计数相关。进一步地，我们表明PET成像容易监测受受体阻断作用的药代动力学变化。 〜（18）F-Iabel GCase能够通过PET监测体内酶的分布和组织半衰期的能力提供了强大的研究工具，可立即应用于Gaucher病的临床应用，并为应用于其他ERT的明确途径。

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    Christopher P. Phenix; rnBrian P. Rempel; rnKaren Colobong; rnDoris J. Doudet; rnMichael j. Adam; rnLome A. Clarke; rnStephen G. Withers;

  • 作者单位

    Tri-University Meson Facility (TRIUMF), 4004 Wesbrook Mall, Vancouver, BC, Canada V6T 2A3 Departments of Chemistry and Biochemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1;

    rnDepartments of Chemistry and Biochemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1;

    rnChild and Family Research Institute, Department of Medical Genetics, University of British Columbia,950 W28th Avenue, Vancouver, BC, Canada V5Z 4H4;

    rnDepartment of Medicine, Division of Neurology, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5;

    rnTri-University Meson Facility (TRIUMF), 4004 Wesbrook Mall, Vancouver, BC, Canada V6T 2A3;

    rnChild and Family Research Institute, Department of Medical Genetics, University of British Columbia,950 W28th Avenue, Vancouver, BC, Canada V5Z 4H4;

    rnDepartments of Chemistry and Biochemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1;

  • 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
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  • 关键词

    mechanism-based enzyme inhibition; PET Imaging; Lysosomal Storage diseases; Gaucher disease;

    机译：基于机制的酶抑制;PET成像;溶酶体贮积病;高雪氏病;

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