TRAF6 Nanoimmunotherapy to resolve plaque inflammation

TRAF6 纳米免疫疗法解决斑块炎症

• 批准号: 10210324
• 负责人: Zahi A. Fayad
• 金额: $ 81.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10210324
• 关键词: Anti-Inflammatory Agents; 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; Oncology; 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; efficacy evaluation; image guided; imaging modality; immunoregulation; in vivo; macrophage; member; migration; monocyte; mouse model; nanobiologic; nanoparticle; nonhuman primate; novel; pre-clinical; prevent; programs; recruit; research clinical testing; serial imaging; small molecule inhibitor; success

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.

总结 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无法接受。 在本申请中，我们提出巨噬细胞的靶向免疫调节将解决斑块 炎症和有益地影响心肌梗死诱导的单核细胞增多症的有害作用。与 为了达到这个目的，我们开发了一种新的“纳米生物学”，一种我们身体自身高密度的生物工程版本。 脂蛋白（HDL）纳米颗粒，特异性靶向（斑块）骨髓细胞6，7。高密度脂蛋白纳米生物制剂含有 一种小分子抑制剂（TRAF 6 i），针对TRAF 6上的CD 40结合结构域， 阻断CD 40-TRAF 6相互作用。 基于Apoe-/-小鼠和非人灵长类动物的这些初步数据，我们提出-在两个 独立特定目的-TRAF 6 i-HDL应用于（i）预防动脉粥样硬化斑块恶化， 在Apoe-/-小鼠中诱导心肌梗死和（ii）在非人灵长类动物中诱导斑块消退 动脉粥样硬化模型 在目标1中，我们将进行一项纵向和成像引导的治疗研究，包括为期一周的高剂量 以及在动脉粥样硬化Apoe-/-小鼠中的四周低剂量TRAF 6 i-HDL方案。在相同的小鼠模型中，我们 将应用TRAF 6 i-HDL纳米免疫疗法预防心肌梗死后斑块加重， 防止炎性单核细胞在血管壁中的有害积累。在目标2中，根据我们的 广泛的小鼠功效数据和非人灵长类动物中的成像数据，我们将使用TRAF 6 i-HDL纳米- 免疫疗法以使非人灵长类动物中建立的斑块消退。正电子发射断层扫描， 磁共振成像（PET/MRI）方法将作为TRAF 6 i-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 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翻译铺平道路。