Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance

长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗

• 批准号: 10424582
• 负责人: Jinjun Shi
• 金额: $ 68.72万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10424582
• 关键词: Acetylgalactosamine; Address; Apoptotic; Area; Arterial Fatty Streak; Atherosclerosis; Biocompatible Materials; Blood; Blood Circulation; Blood coagulation; Calcium; Calmodulin; Cardiometabolic Disease; Categories; Cause of Death; Cells; Cessation of life; Chemicals; Chemistry; Chronic Disease; Clinical; Complex; Coronary heart disease; Dangerousness; Development; Disease; Dose; Drug Kinetics; Engineering; FDA approved; Formulation; Frequencies; Galactose; Gene Silencing; Generations; Genes; Genetic Diseases; Goals; Half-Life; Hepatocyte; Human; Impairment; In Vitro; Individual; Inflammation; Injections; Insulin Resistance; Lead; Lesion; Ligands; Lipids; Liver; Mediating; Mediator of activation protein; Modeling; Modification; Mus; Myocardial Infarction; Nanotechnology; Nature; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Peptides; Phagocytosis; Pharmaceutical Preparations; Phosphotransferases; Process; RNA Interference; RNA Interference Therapy; RNA delivery; Resolution; Safety; Science; Series; Small Interfering RNA; Surface; System; Technology; Testing; Therapeutic; Thick; Work; base; clinical development; effective therapy; efficacy evaluation; ethylene glycol; improved; in vivo; in vivo Model; lead candidate; lipid nanoparticle; macrophage; mortality; mouse model; nanoparticle; novel; obesity treatment; success; surface coating; therapeutic RNA; therapeutic target; uptake; western diet

ABSTRACT With the ability to silence individual genes and to drug the ‘undruggable’, RNA interference (RNAi) therapy has recently shown clinical success by delivering small interfering RNA (siRNA) to the liver for genetic diseases. However, new delivery strategies will be needed to expand the targeting possibilities of siRNA therapy beyond the liver for treatment of other diseases like atherosclerotic cardiovascular disease. We have therefore formed a team with complementary expertise in siRNA delivery and atherosclerosis, and developed a targeted siRNA delivery strategy to silence calcium/calmodulin-dependent kinase-IIγ (CaMKIIγ), a kinase that is activated in the macrophages of human and mouse advanced atherosclerotic lesions and promotes progression of clinically dangerous plaques. We showed that targeted siCamk2g treatment improved plaque stability by reducing necrotic core area and increasing fibrous cap thickness. Nevertheless, due to the transient nature of siRNA-mediated gene silencing, a critical challenge for siRNA therapy is the short duration of action. In this project, we propose to i) explore a novel siRNA delivery strategy that can dramatically extend the duration of CaMKIIγ silencing in atherosclerotic lesional macrophages; and ii) engineer the new siCamk2g platform for dual-cell targeting for integrated treatment of obesity-induced type 2 diabetes and atherosclerosis. Our new preliminary work has identified a distinct type of synthetic lipid-poly(ethylene glycol) (lipid-PEG) biomaterials that can markedly prolong siRNA silencing and its blood circulation. We thus hypothesize that the new lipid-PEG-mediated long-acting siCamk2g therapy could effectively target both atherosclerosis and insulin resistance with low dosing frequency. In Aim 1, we will synthesize a series of such distinct lipid-PEG biomaterials; systematically explore the lipid-PEG effects on the duration of action and pharmacokinetics of siRNA; and optimize the unique siRNA delivery platform in a mouse model with established atherosclerosis. The lead candidate with longest duration of macrophage CaMKIIγ silencing will be evaluated for efficacy in dampening atherosclerosis, with an emphasis on plaque necrosis, fibrous cap thickness, and efferocytosis and other inflammation resolution endpoints. In Aim 2, we will expand the long-acting siRNA therapy to dual-cell targeting for cardiometabolic disease, based upon the fact that CaMKIIγ is a common upstream target in both hepatocytes in obesity-induced insulin resistance and lesional macrophages in atherosclerosis. We will iteratively optimize the dual-targeting siCamk2g system in vitro and in vivo, including in a new mouse model with combined insulin resistance and atherosclerosis, in a manner to effectively improve type 2 diabetes and suppress atherosclerosis. We expect that successful completion of this project will lead to fundamental understanding of how the new lipid-PEG chemistry controls siRNA delivery and the development of a novel class of long-acting RNAi therapy for atherosclerosis and cardiometabolic disease.

抽象的 RNA 干扰 (RNAi) 疗法能够沉默单个基因并为“不可成药”药物提供药物， 最近，通过将小干扰 RNA (siRNA) 递送至肝脏治疗遗传性疾病，取得了临床成功。 然而，需要新的递送策略来扩展 siRNA 治疗的靶向可能性 肝脏用于治疗其他疾病，如动脉粥样硬化性心血管疾病。因此我们成立了一个 团队在 siRNA 递送和动脉粥样硬化方面具有互补的专业知识，并开发了靶向 siRNA 沉默钙/钙调蛋白依赖性激酶 IIγ (CaMKIIγ) 的递送策略，这是一种在 人类和小鼠晚期动脉粥样硬化病变的巨噬细胞并促进临床进展 危险的斑块。我们表明，靶向 siCamk2g 治疗通过减少坏死来改善斑块稳定性 核心面积和增加纤维帽厚度。然而，由于 siRNA 介导的瞬时性质 基因沉默，siRNA疗法的一个关键挑战是作用持续时间短。在这个项目中，我们建议 i) 探索一种新的 siRNA 递送策略，可以显着延长 CaMKIIγ 沉默的持续时间 动脉粥样硬化病变巨噬细胞； ii) 设计新的 siCamk2g 平台，用于双细胞靶向 肥胖引起的2型糖尿病和动脉粥样硬化的综合治疗。我们新的前期工作有 确定了一种独特类型的合成脂质聚乙二醇（脂质-PEG）生物材料，可以显着延长 siRNA沉默及其血液循环。因此，我们假设新的脂质-PEG介导的长效 siCamk2g 疗法可以以低给药频率有效针对动脉粥样硬化和胰岛素抵抗。 在目标1中，我们将合成一系列此类独特的脂质-PEG生物材料；系统地探索脂质-PEG 对 siRNA 作用持续时间和药代动力学的影响；并优化独特的siRNA递送平台 在已确定动脉粥样硬化的小鼠模型中。巨噬细胞持续时间最长的主要候选者 将评估 CaMKIIγ 沉默抑制动脉粥样硬化的功效，重点是斑块 坏死、纤维帽厚度、胞吞作用和其他炎症消退终点。在目标 2 中，我们将 基于以下事实，将长效 siRNA 疗法扩展到双细胞靶向治疗心脏代谢疾病 CaMKIIγ 是肥胖引起的胰岛素抵抗和病变肝细胞中常见的上游靶标 动脉粥样硬化中的巨噬细胞。我们将在体外和体内迭代优化双靶向siCamk2g系统 体内，包括在具有胰岛素抵抗和动脉粥样硬化相结合的新小鼠模型中， 有效改善2型糖尿病，抑制动脉粥样硬化。我们期待本次活动的顺利完成 该项目将导致人们对新的脂质-PEG化学如何控制 siRNA 递送和 开发一类针对动脉粥样硬化和心脏代谢疾病的新型长效 RNAi 疗法。