Base editing of ASGR1 for cardiovascular disease

ASGR1 碱基编辑治疗心血管疾病

• 批准号: 10590146
• 负责人: Renzhi Han
• 金额: $ 19.81万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-17 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590146
• 关键词: ANGPTL3 gene; Adenine; American; Arterial Fatty Streak; Atherosclerosis; Benchmarking; Biochemical; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cells; Cessation of life; Cholesterol; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; Communication; Complex; Consumption; Coronary Arteriosclerosis; Coronary Occlusions; Coronary heart disease; DNA; DNA Double Strand Break; DNA Sequence Alteration; Dangerousness; Dependovirus; Development; Dietary Fats; Disease; Duchenne muscular dystrophy; Dyslipidemias; Dystrophin; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Event; Genes; Genomic DNA; Guide RNA; Heart; Heart Diseases; High Density Lipoproteins; High Fat Diet; Histologic; Hyperlipidemia; Hypertriglyceridemia; Immune response; Incidence; Knockout Mice; LDL Cholesterol Lipoproteins; Lesion; Light; Lipids; Liver; Low-Density Lipoproteins; Measurement; Mediating; Medicine; Molecular; Mus; Mutation; Myocardial Infarction; Nature; Nonsense Mutation; Organ; Patients; Pharmaceutical Preparations; Physiological; Plasma; Point Mutation; Publishing; RNA; RNA Editing; Reagent; Residual state; Risk; Risk Factors; Role; Running; Safety; Serology; Specificity; Stains; System; T-Lymphocyte; Technology; Testing; Therapeutic; Therapeutic Effect; United States; Viral Packaging; base editing; base editor; cardiovascular disorder prevention; cardiovascular disorder risk; clinical practice; combat; coronary artery occlusion; deep sequencing; design; empowerment; genetic approach; genetic variant; genome editing; genome wide association study; heart disease risk; hypercholesterolemia; improved; in vivo; inherited cardiomyopathy; inhibitor; lipid metabolism; loss of function mutation; mouse model; new therapeutic target; novel; novel therapeutics; prevent; research and development; restoration; technology platform; therapeutic development; therapeutic genome editing; transcriptome; transcriptome sequencing; transcriptomics; tumorigenic

PROJECT SUMMARY Heart diseases are the number one leading cause of death in the United States and worldwide, responsible for over 655,000 American deaths each year. The most prevalent cardiovascular diseases (CVD) such as coronary artery disease (CAD) arise from the interplay between complex genetic variants and environmental factors. In particular, the low-density lipoproteins (LDL) is critical contributing factor to atherosclerosis and increased risk of CVD. The use of statin drugs considerably reduced the incidence of CVD. Despite the enormous progress of clinical practice in the past 30 years, insufficient LDL-cholesterol reduction and relatively high residual risk remains for a significant proportion of statin-treated patients with or without combination therapy, likely due to persistent relatively high triglyceride (TG) levels. This underscores the need for additional new therapies targeting lipid metabolism in CVD prevention and treatment. Recent advances in genome editing technologies, in particular the base editors, empower us to explore the feasibility of precise correction of genetic mutations for genetic cardiomyopathy such as Duchenne muscular dystrophy (DMD). In a mouse model of DMD, we recently achieved a near complete dystrophin restoration in the heart after a systemic delivery of adenine base editor and the gRNA with adeno-associated virus 9 (AAV9). Leveraging this exciting advancement in the in vivo base editing technology, here we will develop more broadly applicable therapeutic strategies to combat CVD in a “hit-and-run” fashion (a technology we referred to as diBE), thus minimizing the potential risks associated with AAV-mediated persistent expression of base editing reagents, which are known to have intrinsic off-target DNA and RNA editing activities. We will determine the therapeutic potential of diBE- mediated silencing of Asgr1 for protection against high fat diet induced hypercholesterolemia and atherosclerosis in mice. Completion of these studies will have a high potential for making a major impact on the development of novel base editing therapies to treat hyperlipidemia and CVD.

项目概要 心脏病是美国和世界范围内第一大死亡原因， 每年有超过 655,000 名美国人死亡。最常见的心血管疾病 (CVD)，例如 冠状动脉疾病 (CAD) 是由复杂的遗传变异和环境之间的相互作用引起的 因素。特别是低密度脂蛋白（LDL）是动脉粥样硬化和动脉粥样硬化的关键因素。 CVD 风险增加。他汀类药物的使用大大降低了CVD的发病率。尽管 过去 30 年来临床实践取得了巨大进步，但 LDL 胆固醇降低不足且相对 对于相当比例的他汀类药物联合治疗或不联合治疗的患者来说，仍然存在高残留风险 治疗，可能是由于甘油三酯（TG）水平持续相对较高。这强调了需要额外 针对心血管疾病预防和治疗中脂质代谢的新疗法。基因组的最新进展 编辑技术，特别是碱基编辑器，使我们能够探索精确校正的可行性 遗传性心肌病的基因突变，例如杜氏肌营养不良症（DMD）。在小鼠中 DMD 模型，我们最近在全身性治疗后实现了心脏中几乎完全的肌营养不良蛋白恢复 使用腺相关病毒 9 (AAV9) 递送腺嘌呤碱基编辑器和 gRNA。利用这一激动人心的 随着体内碱基编辑技术的进步，我们将开发更广泛适用的治疗药物 以“肇事逃逸”方式对抗 CVD 的策略（我们称为 diBE 的技术），从而最大限度地减少 与已知的 AAV 介导的碱基编辑试剂持续表达相关的潜在风险 具有内在的脱靶 DNA 和 RNA 编辑活性。我们将确定 diBE-的治疗潜力 介导的 Asgr1 沉默可预防高脂肪饮食引起的高胆固醇血症和 小鼠动脉粥样硬化。完成这些研究将很有可能对世界产生重大影响。 开发治疗高脂血症和心血管疾病的新型碱基编辑疗法。