Therapeutic efficiency of vector-expressed soluble virus receptor proteins in cardiac enterovirus infections

载体表达的可溶性病毒受体蛋白对心脏肠道病毒感染的治疗效果

• 批准号: 107641996
• 负责人: Dr. Henry Fechner
• 金额: --
• 依托单位: Fachgebiet Angewandte Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/107641996?language=en
• 关键词: Therapeutic; efficiency; vector; expressed; soluble

Coxsackieviruses (CV) are the most common infectious agents causing virus-induced myocarditis. A specific CV therapy, however, is currently not yet available. The development of new therapeutic strategies is therefore of high relevance and represents the main objective of this project proposal. In the first funding period we have shown that a soluble CV receptor protein (sCAR-Fc) expressed from a viral vector inhibits acute CVB3 myocarditis and the development of cardiac dysfunction in vivo. Moreover, application of sCAR-Fc was sufficient to cure a newly established persistently CVB3-infected myocardial cell line. In a further study we have demonstrated that the efficiency of sCAR-Fc therapy can be improved by concomitant administration of anti-CVB3 siRNAs. Finally, we have shown for the first time that CVB3-induced myocarditis can be improved by cell therapy with mesenchymal stem cells and cardiac adherent proliferating cells.The project proposal for the second funding period involves five complexes with the following aims. (I) After having demonstrated the effectiveness of sCAR-Fc therapy in acute CVB3-induced myocarditis, we now want to investigate the therapeutic potential of sCAR-Fc in chronic myocarditis. (II) Virus-induced as well as reactive immunologic mechanisms are important mechanisms for the development of chronic CVB3-induced myocarditis. We will determine the extent to which the combination of antiviral therapy with sCAR-Fc and immunosuppressive pharmacotherapy and immunomodulatory stem cell therapy results in an improvement of the therapeutic efficiency. (III) Picornaviruses, among them CVB3, rapidly develop escape mutants following pharmacotherapy. However, there are thus far no studies investigating the occurrence of sCAR-Fc-resistant CVB3 mutants. We intend to analyze CVB3 isolates from sCAR-Fc-treated, CVB3-infected mice for sCAR-Fc-resistant mutants. Furthermore, sCAR-Fc escape mutants will be deliberately generated in vitro and the mechanisms for the development of resistance will be investigated. (IV) We have shown that the D2 domain of CAR, which is not directly involved in binding to CVB3, is important for the CVB3 neutralizing properties of sCAR-Fc. We will further elucidate the function of the D2 domain and the involved mechanisms. (V) Finally, since there are no data available to date, we intend to investigate CVB3 isolates from patients for susceptibility to sCAR-Fc. The expected results may be highly relevant for a potential clinical therapeutic application of sCAR-Fc.

柯萨奇病毒（CV）是引起病毒性心肌炎最常见的病原体。然而，目前还没有特定的CV治疗。因此，开发新的治疗策略具有高度相关性，是本项目提案的主要目标。在第一个资助期内，我们已经证明，从病毒载体表达的可溶性CV受体蛋白（sCAR-Fc）可抑制急性CVB 3心肌炎和体内心功能障碍的发展。此外，sCAR-Fc的应用足以治愈新建立的持续CVB 3感染的心肌细胞系。在进一步的研究中，我们已经证明sCAR-Fc治疗的效率可以通过伴随施用抗CVB 3 siRNA来提高。最后，我们首次证明了用间充质干细胞和心脏贴壁增殖细胞进行细胞治疗可以改善CVB 3诱导的心肌炎。第二个资助期的项目建议书包括五个复合物，目标如下。(I)在证明了sCAR-Fc治疗急性CVB 3诱导的心肌炎的有效性后，我们现在想研究sCAR-Fc在慢性心肌炎中的治疗潜力。(II)病毒诱导和反应性免疫机制是慢性CVB 3诱导心肌炎发生的重要机制。我们将确定抗病毒治疗与sCAR-Fc和免疫抑制药物治疗和免疫调节干细胞治疗的组合导致治疗效率改善的程度。(III)小核糖核酸病毒，其中包括CVB 3，在药物治疗后迅速发展逃逸突变体。然而，迄今为止还没有研究sCAR-Fc抗性CVB 3突变体的发生。我们打算分析来自sCAR-Fc处理的CVB 3感染小鼠的CVB 3分离株的sCAR-Fc抗性突变体。此外，将在体外有意产生sCAR-Fc逃逸突变体，并研究耐药性产生的机制。(IV)我们已经表明，CAR的D2结构域（其不直接参与与CVB 3的结合）对于sCAR-Fc的CVB 3中和特性是重要的。我们将进一步阐明D2结构域的功能和相关机制。(V)最后，由于迄今为止没有可用的数据，我们打算研究来自患者的CVB 3分离株对sCAR-Fc的敏感性。预期结果可能与sCAR-Fc的潜在临床治疗应用高度相关。

项目成果

Combination of RNA interference and virus receptor trap exerts additive antiviral activity in coxsackievirus B3-induced myocarditis in mice.

• DOI: 10.1093/infdis/jiu504
• 发表时间: 2015-02
• 期刊: The Journal of infectious diseases
• 作者: E. A. Stein;S. Pinkert;P. Becher;Anja Geisler;H. Zeichhardt;R. Klopfleisch;W. Poller;C. Tschöpe;D. Lassner;H. Fechner;J. Kurreck

Expression of an engineered soluble coxsackievirus and adenovirus receptor by a dimeric AAV9 vector inhibits adenovirus infection in mice

二聚体 AAV9 载体表达工程化可溶性柯萨奇病毒和腺病毒受体可抑制小鼠体内的腺病毒感染

• DOI: 10.1038/gt.2015.19
• 发表时间: 2015
• 期刊: Gene Therapy
• 影响因子: 5.1
• 作者: Röger C;Pozzuto T;Klopfleisch R;Kurreck J;Pinkert S;Fechner H
• 通讯作者: Fechner H

Enhanced suppression of adenovirus replication by triple combination of anti-adenoviral siRNAs, soluble adenovirus receptor trap sCAR-Fc and cidofovir.

通过抗腺病毒 siRNA、可溶性腺病毒受体捕获 sCAR-Fc 和西多福韦的三重组合增强对腺病毒复制的抑制

• DOI: 10.1016/j.antiviral.2015.05.010
• 发表时间: 2015
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Pozzuto T;Roger C;Kurreck J;Fechner H
• 通讯作者: Fechner H

The Coxsackievirus and Adenovirus Receptor: Glycosylation and the Extracellular D2 Domain Are Not Required for Coxsackievirus B3 Infection

柯萨奇病毒和腺病毒受体：柯萨奇病毒 B3 感染不需要糖基化和胞外 D2 结构域

• DOI: 10.1128/jvi.00315-16
• 发表时间: 2016
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Pinkert S;Röger C;Kurreck J;Bergelson J;Fechner H
• 通讯作者: Fechner H