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 心肌梗塞（MI）后，基质衍生的因子1α（SDF-1α）迅速增加，已显示 为了增加微血管密度，降低梗塞大小，抑制边界区域扩展并减轻广告 重塑以保留缺血性心脏组织。但是，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。对抗这一点 局限性，几个小组研究了SDF-1α的外源递送。发现早期 外源SDF-1α的递送增加了内源性修复过程，而SDF-1α的后期增加 被证明可以改善心脏功能。这些研究激发了一种治疗方法来提供持续的 SDF-1α传递和功能益处，在父项目中进行了研究。 尽管短期外源性SDF-1α的递送导致了令人鼓舞的结果，但对这些影响知之甚少 急性MI后，持续的SDF-1α递送到心肌中。对这些影响的进一步研究是 父母项目的重要逻辑扩展和不可或缺的组件，因为它可能完全不同 SDF-1α短期治疗的影响。此外，虽然SDF-1α基因疗法的单次递送已经 在临床研究并证明有希望的结果中，这些疗法是在盐水中递送的。所以， 关于重复分娩基因疗法是否会进一步改善心脏的挥之不去的问题 功能。为了持续递送SDF-1α进入临床研究，需要其他信息以更好 了解其影响，作用机理以及任何可能的不利影响。 为了实现这一目标，我们建议扩展到母公司项目的目标3。在那里，我们建议使用 弹性蛋白样蛋白质 - 溶甲酸（ELP-HA）水凝胶配方，该配方在体外优化了 持续的SDF-1α微圆（MC）基因释放，在体内临床前评估心脏功能恢复中。 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。调查任何再生的可能机制 我们看到，我们将对细胞因子分泌以及RNA测序（RNASEQ）进行蛋白质组学分析。最后， 由于已知SDF-1α及其受体CXCR4在缺血性的干细胞寄养中起重要作用 心肌，我们将研究其趋化性潜力，以绘制内源性内源祖细胞 （EPC）。我们的研究结果不仅会在SDF-1α的持续递送对血管有益的情况下告知我们 MI之后的心脏再生，以及SDF-1α提供其益处的机制。这 多样性补充剂将使代表性不足的少数学员的研究职业发展到 过渡到独立。