Injectable Hydrogels to Deliver Gene Therapy for Myocardial Infarct

可注射水凝胶为心肌梗塞提供基因治疗

• 批准号: 10732139
• 负责人: Sarah C Heilshorn
• 金额: $ 2.9万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10732139
• 关键词: Acute myocardial infarction; Adverse effects; Attenuated; Blood Vessels; CXCR4 Receptors; Cardiac; Catheters; Clinical; Clinical Research; Clinical Trials; Coronary; Elastin; Formulation; Gel; Gene Delivery; Genes; Goals; Heart; Homing; Human; Hyaluronic Acid; Hydrogels; Immunofluorescence Immunologic; Immunohistochemistry; In Vitro; Infarction; Injectable; Injections; Investigation; Ligation; Modeling; Morphology; Myocardial Infarction; Myocardial Ischemia; Myocardium; Natural regeneration; Peptides; Play; Pre-Clinical Model; Process; Proteins; Proteomics; Rattus; Recovery of Function; Research; Role; Saline; Signal Transduction; System; Therapeutic; Tissues; Underrepresented Minority; Up-Regulation; Vascular regeneration; animal tissue; cardiac regeneration; career; combat; cytokine; density; endothelial stem cell; gene therapy; heart function; improved; in vivo; minority trainee; parent project; pre-clinical assessment; preservation; repaired; stem cells; tissue repair; transcriptome sequencing

Project Summary Stromal derived factor-1α (SDF-1α) rapidly increases following myocardial infarction (MI) and has been shown to increase microvascular density, reduce infarct size, inhibit border zone expansion, and attenuate adverse remodeling to preserve the ischemic cardiac tissue. However, this intrinsic upregulation is transient, and the protective function of SDF-1α quickly declines, thereby reducing the potential for tissue repair. To combat this limitation, several groups have investigated the exogenous delivery of SDF-1α. It was found that early-stage delivery of exogenous SDF-1α augmented the endogenous repair process, while late-stage increase in SDF-1α was shown to improve cardiac function. These studies motivate a therapeutic approach to provide sustained SDF-1α delivery and functional benefit, which is investigated in the parent project. Despite encouraging results from short-term exogenous SDF-1α delivery, little is known about the effects of sustained SDF-1α delivery into the myocardium following acute MI. Further investigation of these effects is an important logical extension and integral component of the parent project, as it may be completely distinct from the effects of short-term treatment with SDF-1α. Further, while single delivery of SDF-1α gene therapy is already in clinical studies and demonstrate promising results, these therapies were delivered in saline. Therefore, lingering questions remain as to whether repeated delivery of the gene therapy would further improve cardiac function. For sustained delivery of SDF-1α to enter clinical studies, additional information is necessary to better understand its effects, mechanism of action, as well as any possible adverse effects. Towards this goal, we propose an extension to Aim 3 of the parent project. There, we proposed to use the elastin-like protein-hyaluronic acid (ELP-HA) hydrogel formulation, which has been optimized in vitro for sustained SDF-1α minicircle (MC) gene release, in an in vivo preclinical assessment of cardiac function recovery. In this Diversity Supplement project, we will evaluate the in vivo vascular regeneration of the heart following MI through immunohistochemistry of cardiac tissue. To investigate possible mechanism(s) of any regeneration that we see, we will perform proteomic profiling of cytokine secretions as well as RNA sequencing (RNASeq). Finally, since SDF-1α and its receptor CXCR4 is known to play an important role in stem cell homing to the ischemic myocardium, we will investigate its chemoattractive potential to draw endogenous endothelial progenitor cells (EPCs). The results of our study will inform us not only if sustained delivery of SDF-1α is beneficial to vascular and cardiac regeneration following MI, but also the mechanism by which SDF-1α delivers its benefits. This Diversity Supplement will advance the research career of an underrepresented minority trainee towards the transition to independence.

项目摘要 基质衍生因子-1 α（SDF-1α）在心肌梗死（MI）后迅速升高， 增加微血管密度，减少梗死面积，抑制边缘区扩张， 重塑以保护缺血的心脏组织。然而，这种内在的上调是短暂的， SDF-1α的保护功能迅速下降，从而降低了组织修复的潜力。打击这一 由于其局限性，几个研究小组已经研究了SDF-1α的外源性递送。结果发现， 外源性SDF-1α的递送增强了内源性修复过程，而后期SDF-1α的增加 可以改善心脏功能这些研究激发了一种治疗方法， SDF-1α的递送和功能获益，在母项目中进行了研究。 尽管短期外源性SDF-1α给药的结果令人鼓舞， 急性心肌梗死后持续SDF-1α进入心肌。对这些影响的进一步研究是 父项目的重要逻辑扩展和组成部分，因为它可能完全不同于 SDF-1α短期治疗的效果。此外，虽然SDF-1α基因治疗的单次递送已经被证实是有效的。 在临床研究中，这些疗法在盐水中递送，并显示出有希望的结果。因此，我们认为， 关于重复基因治疗是否会进一步改善心脏病的问题仍然存在。 功能对于持续递送SDF-1α进入临床研究，需要更多信息以更好地 了解其影响、作用机制以及任何可能的不良影响。 为了实现这一目标，我们提出了一个扩展的父项目的目标3。在那里，我们建议使用 弹性蛋白样蛋白-透明质酸（ELP-HA）水凝胶制剂，其已经在体外优化， 持续SDF-1α小环（MC）基因释放，用于心功能恢复的体内临床前评估。 在这个多样性补充项目中，我们将评估MI后心脏的体内血管再生 通过心脏组织的免疫组织化学。研究任何再生的可能机制， 我们看到，我们将进行细胞因子分泌的蛋白质组学分析以及RNA测序（RNASeq）。最后， 由于已知SDF-1α及其受体CXCR 4在干细胞归巢至缺血性脑损伤中起重要作用， 心肌，我们将研究其化学吸引潜力，以吸引内源性内皮祖细胞 （EPC）。我们的研究结果将告诉我们，持续输送SDF-1α不仅有益于血管内皮细胞， 以及心肌梗死后的心脏再生，以及SDF-1α发挥作用的机制。这 多样性补充将推进一个代表性不足的少数民族学员的研究生涯， 过渡到独立。