Targeted cell therapy for the treatment of ventricular tachycardia

描述（由申请人提供）： 该申请涉及广泛的挑战领域（11）：再生医学和特定的挑战主题，11-HL-101：开发基于细胞的治疗心血管，肺和血液疾病。心肌梗死（MI）引起的心源性猝死（SCD）是心脏病死亡的最常见原因。目前的治疗，如植入式心律转复除颤器和抗心律失常药物是姑息性的，往往会引起危及生命的心律失常。射频导管消融术可以治疗心肌梗死相关心律失常，但许多患者不适用，复发率高。因此，SCD仍然是一个尚未解决的重大公共卫生问题。在许多患有慢性愈合的MI的患者中，SCD是由于瘢痕组织附近的异常电脉冲传导引起的折返性室性心动过速（VT）。直接针对这种异常电基质的治疗可能会降低VT的发生率。例如，RF消融通过永久性破坏对折返回路至关重要的组织来靶向基底。然而，这种方法扩大了坏死超过预先存在的疾病引起的疤痕，这可能解释了为什么这种疗法并不总是成功的。我们提出了一种新的范式来应对这一挑战：而不是破坏更多的组织和创造额外的异常传导区域，一种更有效的方法来治愈VT是使用靶向细胞治疗恢复正常传导到折返回路的关键区域。细胞疗法似乎是一种有前途的治疗与急性心肌梗死相关的心肌修复。重要的是，我们实验室使用间充质干细胞（MSC）治疗的研究表明，瘢痕组织中的电活力可以部分恢复，部分原因是所施用细胞的直接作用。此外，间接（旁分泌）效应，如干细胞募集，可以通过释放细胞信号，如SDF-1诱导。然而，促进这种旁分泌作用的化学信号在慢性愈合的MI中不存在。这种情况和直接注射的细胞的不良保留对存活、植入以及最终在愈合的MI的情况下恢复瘢痕组织的电活力产生了几个障碍。我们假设靶向细胞治疗可用于恢复折返回路关键通路中的冲动传播，并预防与慢性MI相关的VT;然而，需要稳健的干细胞植入和募集。我们的目标是确定是否可以使用水凝胶和旁分泌因子增强慢性MI中干细胞的植入和募集。我们还将确定干细胞治疗是否可以消除慢性MI/VT临床相关模型中的慢传导并降低VT易感性。该提案的长期目标是创建一种新型有效的治疗VT的范例，该范例可以轻松地过渡到临床试验，并最终改变有SCD风险的MI患者的护理标准。 公共卫生相关性：在美国，每年有数十万人遭受心脏性猝死（SCD）。目前植入式心律转复除颤器、抗心律失常药物治疗和射频导管消融治疗SCD的潜在病理生理原因无效。因此，SCD仍然是一个尚未解决的重大公共卫生问题。该提案提出了一种使用靶向细胞治疗来恢复正常功能的新方法，从而治愈了许多有SCD风险的患者。1

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (11): Regenerative Medicine and specific Challenge Topic, 11-HL-101: Develop cell-based therapies for cardiovascular, lung, and blood diseases. Sudden cardiac death (SCD) due to myocardial infarction (MI) is the most common cause of mortality from heart disease. Current therapies such as implantable cardioverter defibrillators and antiarrhythmic drugs are palliative and often provoke life-threatening cardiac arrhythmias. Radiofrequency (RF) catheter ablation can cure arrhythmias associated with MI; however, many patients are not suitable and the recurrence rate is high. Consequently, SCD remains a major unresolved public health problem. In many patients with chronically healed MI, SCD is due to reentrant ventricular tachycardia (VT) caused by abnormal electrical impulse conduction in the vicinity of scar tissue. Therapy that directly targets this abnormal electrical substrate may decrease the incidence of VT. For example, RF ablation targets the substrate by permanently destroying tissue critical to the reentrant circuit. However, this procedure expands necrosis beyond the preexisting disease-induced scar, which may explain why this therapy is not always successful. We propose a novel paradigm to address this challenge: rather than destroying more tissue and creating additional areas of abnormal conduction, a more efficacious approach to cure VT is to restore normal conduction to critical regions of the reentrant circuit using targeted cell therapy. Cell therapy appears as a promising treatment for myocardial repair associated with acute MI. Importantly, studies from our laboratory using mesenchymal stem cell (MSC) therapy have shown that electrical viability in scar tissue can be partially restored due to, in part, a direct effect of the cells administered. Additionally, indirect (paracrine) effects, such as stem cell recruitment, can be induced by the release of cellular signals such as SDF-1. However, the chemical signals that promote such paracrine effects are absent in chronically healed MI. This and poor retention of cells that are directly injected create several barriers to the survival, engraftment, and ultimately the restoration of electrical viability of scar tissue in the setting of healed MI. We hypothesize that targeted cell therapy can be used to restore impulse propagation in pathways critical to the reentrant circuit and prevent VT associated with chronic MI; however, robust stem cell engraftment and recruitment will be required. Our objectives are to determine if the engraftment and recruitment of stem cells in chronic MI can be enhanced using hydrogels and paracrine factors. We will also determine if stem cell therapy can abolish slow conduction and reduce susceptibility to VT in a clinically relevant model of chronic MI/VT. The long term goal of this proposal is to create a novel and efficacious paradigm for treating VT that can be easily transitioned to clinical trials and, eventually, transform the standard of care for patients with MI at risk for SCD. PUBLIC HEALTH RELEVANCE: Several hundred thousand people suffer sudden cardiac death (SCD) each year in the United States. Current treatment with implantable cardioverter defibrillators, antiarrhythmic drug therapy, and radio frequency catheter ablation are ineffective at treating the underlying pathophysiological causes of SCD. Consequently, SCD remains a major unresolved public health problem. This proposal puts forth a novel method using targeted cellular therapy to restore normal function and, thus, cure many patients at risk for SCD. 1