TRAF6 Nanoimmunotherapy to resolve plaque inflammation

TRAF6 纳米免疫疗法解决斑块炎症

基本信息

批准号：
9761564
负责人：
Zahi A. Fayad
金额：
$ 81.62万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9761564
关键词：
Anti-inflammatory Apolipoprotein E Aptitude Arterial Fatty Streak Atherosclerosis Behavior Binding Biodistribution Biological Assay Biomedical Engineering Cardiovascular system Cells Clinical Coronary Arteriosclerosis Data Disease Dose Event Functional disorder Gene Expression High Density Lipoproteins Image Immune system Immunology Immunology procedure Immunotherapy Impairment Inflammation Inflammatory Interleukin-1 beta Light Lipids Low-Density Lipoproteins Magnetic Resonance Imaging Malignant Neoplasms Modeling Monocytosis Multimodal Imaging Mus Myelogenous Myocardial Infarction Nanoimmunotherapy Patients Placebos Positron-Emission Tomography Pre-Clinical Model Process RNA Recurrence Regimen Safety Seminal Specificity Stroke TNFRSF5 gene TRAF6 gene Techniques Therapeutic Studies Time Translations Treatment Efficacy base clinical translation clinically relevant image guided imaging modality immunoregulation in vivo macrophage member migration monocyte mouse model nanobiologic nanoparticle nonhuman primate novel oncology pre-clinical prevent programs recruit research clinical testing serial imaging small molecule inhibitor success

项目摘要

SUMMARY Atherosclerotic plaque regression as a result of lipid-lowering treatment has been limited at best, with coronary artery disease (CAD) related event rates remaining unacceptably high. In this application, we propose that targeted immunomodulation of macrophages will resolve plaque inflammation and beneficially impacts myocardial infarction-induced monocytosis’ detrimental effects. To that aim, we have developed novel ‘nanobiologic’, a bioengineered version of our body’s own high density lipoprotein (HDL) nanoparticle that specifically targets (plaque) myeloid cells6,7. The HDL nanobiologic contains a small molecule inhibitor (TRAF6i), directed against the binding domain of CD40 on TRAF6, to specifically block CD40-TRAF6 interactions. Based on these preliminary data in Apoe–/– mice and nonhuman primates, we propose — in two independent Specific Aims — TRAF6i-HDL’s application to (i) prevent atherosclerotic plaque aggravation due to myocardial infarction in Apoe–/– mice and (ii) induce plaque regression in a nonhuman primate atherosclerosis model. In Aim 1, we will execute a longitudinal and imaging-guided therapeutic study, involving a one-week high-dose and a four-week low-dose TRAF6i-HDL regimen in atherosclerotic Apoe–/– mice. In the same mouse model, we will apply TRAF6i-HDL nano-immunotherapy to prevent plaque aggravation after myocardial infarction, by preventing the detrimental accumulation of inflammatory monocytes in the vessel wall. In Aim 2, based on our extensive mouse efficacy data and imaging data in nonhuman primates, we will employ TRAF6i-HDL nano- immunotherapy to regress established plaques in nonhuman primates. Positron emission tomography with magnetic resonance imaging (PET/MRI) methods will serve as readouts for TRAF6i-HDL’s in vivo behavior and therapeutic efficacy. In light of the promising CANTOS trial data, demonstrating a reduction in recurrent rates in cardiovascular patients that were treated with a targeted anti-inflammatory therapy, successful completion of this application’s aims will pave the way for potential clinical translation.

概括降脂治疗导致的动脉粥样硬化斑块消退充其量是有限的，冠状动脉疾病（CAD）相关事件发生率仍然高得令人难以接受。在此应用中，我们建议巨噬细胞的靶向免疫调节将解决斑块炎症并有益地影响心肌梗死引起的单核细胞增多症的疼痛效果。我们的目标是开发出新型“纳米生物学”，这是我们身体自身高密度的生物工程版本 HDL 纳米生物制剂含有专门针对（斑块）骨髓细胞的脂蛋白 (HDL) 纳米颗粒6,7。一种小分子抑制剂 (TRAF6i)，针对 TRAF6 上 CD40 的结合域，特异性阻断 CD40-TRAF6 相互作用。基于 Apoe–/– 小鼠和非人类灵长类动物的这些初步数据，我们提出——分两种独立的具体目标 — TRAF6i-HDL 的应用是 (i) 预防由于动脉粥样硬化斑块恶化导致 Apoe–/– 小鼠心肌梗塞，并且 (ii) 诱导非人灵长类动物斑块消退动脉粥样硬化模型。在目标 1 中，我们将执行一项纵向和影像引导的治疗研究，包括为期一周的高剂量治疗在同一小鼠模型中，我们对动脉粥样硬化 Apoe-/- 小鼠进行为期 4 周的低剂量 TRAF6i-HDL 治疗。将应用TRAF6i-HDL纳米免疫疗法预防心肌梗塞后斑块加重，通过根据我们的目标 2，防止炎症单核细胞在血管壁中不健康地积聚。大量的小鼠功效数据和非人类灵长类动物的成像数据，我们将采用 TRAF6i-HDL nano- 免疫疗法可消退非人类灵长类动物中已形成的斑块。磁共振成像 (PET/MRI) 方法将作为 TRAF6i-HDL 体内行为的读数和治疗效果。鉴于有希望的 CANTOS 试验数据，表明复发率降低接受靶向抗炎治疗的心血管患者，成功完成该应用程序的目标将为潜在的临床转化铺平道路。