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Tailor-made therapy for patients with septic multiple organ failure using a cytokine adsorbing column based on genetic analysis of cytokine related gene polymorphisms

基于细胞因子相关基因多态性遗传分析的细胞因子吸附柱为脓毒症多器官功能衰竭患者量身定制治疗

基本信息

批准号：
16390514
负责人：
ODA Shigeto
金额：
$ 7.36万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

This study was conducted to establish a novel tailor-made therapy for prevention of septic multiple organ failure (MOF) with anti-cytokine strategy, such as an cytokine adsorbing column, based on the screening of genetically high risk patients of hypercytokinemia using an genetic analysis of cytokine-related genes. To identify the highly related genetic polymorphisms with hypercytokinemia, various reported genetic polymorphisms were analyzed in patients with hypercytokinemia in relation to their clinical course and outcome. Among genetic polymorphisms tested, TNF α-308G/A, IL-1β-511T/A, IL-1ra VNTR polymorphisms were identified to be highly related with uncontrolled hypercytokinemia and poor outcome. We established the screening system to analyze these polymorphisms using real-time PCR in the laboratory within 4-6 hours. To develop a more effective cytokine modulator than PMMA-CHDF, the phase II clinical trial of a newly developed cytokine adsorbing column, CYT-860, in patients with persistent and severe hypercytokinemia was conducted and has been completed. CYT-860-DHP showed significant reduction in cytokine blood levels and resulted in improvement of P/F ratio. Four of 7 enrolled patients were survived and no adverse effect was observed. Further study is needed for clinical approval of this device. As the realistic approach of more potent cytokine modulation, double PMMA-CHDF, in which 2 series of PMMA-CHDF was simultaneously performed, and PMMA-CHDF using a large sized PMMA dialyzer, in which membrane area is double of conventional hemofilter, were evaluated and their efficacy was confirmed clinically. Therefore, we conducted a prospective study to treat patients with hypercytokinemia based on the genetic analysis of cytokine related genes. This tailor-made therapy for hypercytokinemia based on genetic analysis of cytokine-related gene polymorphism has been approved by institute's ethics committee and now on going in our ICU.

本研究旨在通过细胞因子相关基因的遗传分析，筛选高细胞因子血症的遗传高风险患者，建立一种新的抗细胞因子策略，如细胞因子吸附柱，来预防脓毒性多器官衰竭（MOF）。为了确定与高细胞分裂血症高度相关的遗传多态性，我们分析了高细胞分裂血症患者中各种已报道的遗传多态性与其临床病程和结果的关系。在检测的遗传多态性中，TNF α-308G/A、IL-1β-511T/A、IL-1ra VNTR多态性与未控制的高细胞素血症和不良预后高度相关。我们建立了筛选系统，在实验室使用实时PCR在4-6小时内分析这些多态性。为了开发比PMMA-CHDF更有效的细胞因子调节剂，新开发的细胞因子吸附柱CYT-860在持续性和重度高细胞因子血症患者中的II期临床试验已经完成。CYT-860-DHP可显著降低血中细胞因子水平，提高P/F比值。7例入组患者中有4例存活，未观察到不良反应。该装置的临床批准需要进一步研究。作为更有效调节细胞因子的现实途径，我们对双PMMA- chdf进行了评估，其中双PMMA- chdf同时进行了2个系列的PMMA- chdf， PMMA- chdf使用大尺寸PMMA透析器，膜面积是传统血液过滤器的两倍，并对其效果进行了临床验证。因此，我们在对细胞因子相关基因进行遗传分析的基础上，开展了治疗高细胞因子血症患者的前瞻性研究。这种基于细胞因子相关基因多态性遗传分析的高细胞因子血症定制疗法已获得研究所伦理委员会的批准，目前正在我们的ICU进行。