Heart rate control with bioengineered pacemakers

项目总结/摘要 对于有症状的缓慢性心律失常患者，目前唯一的治疗方法是植入电子起搏器， 起搏器。目前几乎所有关于心律管理的研究，包括无导线起搏器， 投资于逐步推进留置装置的消毒。虽然这些设备可以提供稳定的 和长期起搏，该技术远不理想，存在起搏技术固有的问题， 由于留置硬件导致的异物问题。这些问题对于患有以下疾病的儿科患者来说可能很严重： 先天性心脏传导阻滞，因为需要多次侵入性手术来置换或修正植入的 在患者的一生中。与设备相关的急性问题也在增加，包括感染 发生器和/或电极导线，需要通过手术取出整个植入器械。 相比之下，生物工程起搏器通过创建无硬件心脏起搏器， 起搏我们以前已经证明，最小侵入性的天然转录因子基因的传递， 可以在完全心脏传导阻滞的小型和大型动物模型中起搏心室。使能技术 是基于再生组织工程，普通的心肌被转化为专门的 起搏器组织构建体与局部递送的遗传构建体原位结合。为了将这一概念推广到临床 实践中，需要回答两个问题：1）生物工程起搏器能保持功能多久， 以及2）生物工程起搏器在病变心肌中的功能如何，因为大多数患者 心脏起搏器的患者也存在心肌潜在疾病。在本提案中，我们将 直接回答这些问题，采用慢性心脏传导阻滞模型，已知的心脏特征， 失败，并在纵向研究中检查基因治疗的有效性和持久性。

Project Summary/Abstract For patients with symptomatic bradyarrhythmias, the current and only treatment is to implant an electronic pacemaker. Nearly all of the current research regarding rhythm management, including the leadless pacemakers, are invested in incremental progress in miniaturizing the indwelling devices. While the devices can provide stable and long-term pacing, the technology is far from ideal with problems inherent to the pacing technology and to foreign body issues due to the indwelling hardware. The problems can be severe for pediatric patients with congenital heart block as multiple and invasive surgeries are needed for replacement or revision of the implanted devices over the patients’ lifetime. Device-related acute problems are rising as well, include infections with the generator and/or leads wire, which require surgical removal of the entire implanted device. Bioengineered pacemakers, in contrast, transcend all current modalities by creating hardware-free cardiac pacing. We have previously demonstrated that minimally-invasive delivery of a natural transcription factor gene could pace the ventricles in both small and large animal models of complete heart block. The enabling technology is based on regenerative tissue engineering in which ordinary heart muscle is converted to specialized pacemaker tissue construct in situ with a focally delivered genetic construct. To advance this concept to clinical practice, two questions need to be answered: 1) how long can the bioengineered pacemaker retain its function, and 2) how well the bioengineered pacemaker be able to function in diseased myocardium since most patients with a pacemaker are also presented with underlying diseases in the myocardium. In this proposal, we will directly answer these questions by employing chronic heart block models that are known to elicit traits of heart failure, and examining the efficacy and durability of the gene therapy in a longitudinal study.