Development and Application of Optimized Cardio-Specific AdVector-based Systems for In Situ Establishment of Biological Pacemakers

用于生物起搏器原位建立的优化心脏特异性 AdVector 系统的开发和应用

基本信息

项目摘要

Our project addresses the establishment of a "Biological Cardiac Pacemaker" for future therapy of cardiac diseases summarized under the term "Sick-Sinus-Syndrome". We intend to create a biological pacemaker via direct reprogramming of working cardiomyocytes based on the introduction of optimized programming factor combinations. They will be introduced into the target cells via our SMART adenovirus technology, which combines highest specificity, efficacy and safety by tailoring high capacity Ad vectors to bi-specific adaptor proteins, pseudotyping and magnetic nanoparticles. The envisaged approaches allow in situ alterations of cells in vivo. Proof-of-principle will be achieved initially in vitro relying on cultured murine PSC derived cardiomyocytes. Thereby, murine PSC derived pacemaker cells generated via our established forward programming approach will serve as a reference for physiological and functional parameters. The concept will then be translated to a pre-clinical model relying on transgenic mice bearing an experimentally induced Sick-Sinus-Syndrome as well as an ex vivo situation using pig heart slice cultures. Factors, recently newly identified via RNAseq of forward programmed murine pacemaker cells will be included with respect to their applicability in direct reprogramming. The described concept is scientifically unique and of highest clinical relevance.
我们的项目致力于建立一个“生物心脏起搏器”,用于未来治疗“病态-鼻窦综合征”下的心脏病。我们打算在引入优化的编程因子组合的基础上,通过对工作心肌细胞的直接重编程来创造一种生物起搏器。它们将通过我们的SMART腺病毒技术引入靶细胞,该技术通过将高容量Ad载体定制为双特异性适配蛋白、假分型和磁性纳米颗粒,结合了最高的特异性、有效性和安全性。设想的方法允许在体内对细胞进行原位改变。原理证明将首先在体外依靠培养的小鼠PSC衍生心肌细胞实现。因此,通过我们建立的前向编程方法生成的小鼠PSC衍生起搏器细胞将作为生理和功能参数的参考。然后,这一概念将被转化为临床前模型,该模型依赖于携带实验性诱导的疾病-鼻窦综合征的转基因小鼠,以及使用猪心脏切片培养的离体情况。最近通过前向编程小鼠起搏器细胞的RNAseq新发现的因子将包括它们在直接重编程中的适用性。所描述的概念在科学上是独特的,具有最高的临床相关性。

项目成果

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Professor Dr. Robert David其他文献

Professor Dr. Robert David的其他文献

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{{ truncateString('Professor Dr. Robert David', 18)}}的其他基金

Deep sequencing analysis of MesP1 dependent cardiovascular signalling pathways during stem cell differentiation
干细胞分化过程中MesP1依赖性心血管信号通路的深度分析测序
  • 批准号:
    197123046
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
    Research Grants

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