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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要心肌梗塞 (MI) 后基质衍生因子 1α (SDF-1α) 迅速增加，并且已被证明增加微血管密度，减少梗塞面积，抑制边界区扩张，并减轻不良反应然而，这种内在的上调是短暂的，并且 SDF-1α 的保护功能迅速下降，从而降低了组织修复的潜力。由于存在局限性，多个小组研究了 SDF-1α 的外源递送，发现早期阶段。外源性 SDF-1α 的递送增强了内源性修复过程，而 SDF-1α 的后期增加这些研究表明可以改善心脏功能，从而提供持续的治疗方法。 SDF-1α 的递送和功能益处，在父项目中进行了研究。尽管短期外源性 SDF-1α 递送取得了令人鼓舞的结果，但对其效果知之甚少急性 MI 后持续将 SDF-1α 递送至心肌的效果是对这些影响的进一步研究。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此外，SDF-1α 短期治疗的效果已经得到证实。在临床研究中并显示出有希望的结果，这些疗法是在盐水中进行的。重复进行基因治疗是否会进一步改善心脏功能仍是一个挥之不去的问题。为了使 SDF-1α 持续递送进入临床研究，需要更多信息以更好地发挥作用。了解其作用、作用机制以及任何可能的不利影响。为了实现这一目标，我们建议对父项目的目标 3 进行扩展，我们建议使用该目标。类弹性蛋白透明质酸 (ELP-HA) 水凝胶配方，已在体外进行了优化在心脏功能恢复的体内临床前评估中持续 SDF-1α 小环 (MC) 基因释放。在这个多样性补充项目中，我们将评估心肌梗死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，我们将对细胞因子分泌物进行蛋白质组学分析以及 RNA 测序 (RNASeq)。因为已知 SDF-1α 及其受体 CXCR4 在干细胞归巢至缺血区中发挥重要作用心肌，我们将研究其吸引内源性内皮祖细胞的化学吸引潜力（EPC）我们的研究结果不仅会告诉我们持续输送 SDF-1α 是否有益于血管。以及 MI 后的心脏再生，以及 SDF-1α 发挥作用的机制。多样性补充将推动代表性不足的少数族裔实习生的研究生涯走向向独立过渡。