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: 10277786
• 负责人: Jinjun Shi
• 金额: $ 71.13万
• 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/10277786
• 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）具有沉默的单个基因和吸毒的能力，具有 最近通过将小干扰RNA（siRNA）传递到肝脏的遗传疾病来表现出临床成功。 但是，将需要新的交付策略来扩大siRNA治疗的靶向可能性 治疗其他疾病等肝脏等肝脏疾病等疾病。因此，我们已经形成了 团队具有siRNA交付和动脉粥样硬化的完整专业知识，并开发了有针对性的siRNA 递送策略静音钙/钙调蛋白依赖性激酶-IIγ（CAMKIIγ），一种激活的激酶 人和小鼠的巨噬细胞先进的动脉粥样硬化病变，并促进临床上的进展 我们表明，靶向的SICAMK2G治疗通过减少坏死，改善了斑块稳定性 核心区域和增加的纤维帽厚度。然而，由于siRNA介导的短暂性 基因沉默，siRNA治疗的关键挑战是作用时间短。在这个项目中，我们建议 i）探索一种新型的siRNA传递策略，该策略可以极大地延长camkiγ的持续时间 动脉粥样硬化病变巨噬细胞； ii）设计新的SICAMK2G双电池定位平台 肥胖引起的2型糖尿病和动脉粥样硬化的综合治疗。我们的新初步工作 鉴定出一种独特的合成脂质 - 乙二醇（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治疗可以有效地靶向动脉粥样硬化和低给药频率的胰岛素抵抗。 在AIM 1中，我们将合成一系列这种不同的脂质生物材料。系统地探索脂质-PEG 对siRNA的作用和药代动力学的影响；并优化独特的siRNA传递平台 在具有既定动脉粥样硬化的小鼠模型中。巨噬细胞持续时间最长的铅候选人 CAMKIγ沉默将评估以使动脉粥样硬化的效率进行效率，重点是斑块 坏死，纤维帽厚度和肿瘤病和其他感染终点。在AIM 2中，我们将 基于事实 CAMKIIγ是肥胖诱导的胰岛素耐药性和病变的肝细胞中两个常见的上游靶标 动脉粥样硬化中的巨噬细胞。我们将在体外和IN迭代优化双重目标SICAMK2G系统 体内，包括在具有联合胰岛素耐药性和动脉粥样硬化的新小鼠模型中，以一种方式 有效改善2型糖尿病并抑制动脉粥样硬化。我们希望成功完成 项目将导致对新脂质-PEG化学如何控制siRNA的传递和 开发一种新型的长效RNAI治疗，用于动脉粥样硬化和心脏代谢疾病。