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.

项目摘要 心脏病是美国和世界范围内的头号死亡原因， 每年有超过65.5万美国人死亡最常见的心血管疾病（CVD），如 冠状动脉疾病（CAD）是由复杂的遗传变异和环境因素之间的相互作用引起的。 因素特别是，低密度脂蛋白（LDL）是动脉粥样硬化的关键因素， 增加CVD的风险。他汀类药物的使用大大降低了心血管疾病的发生率。尽管 在过去的30年里，临床实践取得了巨大的进步，LDL-胆固醇降低不足， 对于有或无联合用药的他汀类药物治疗患者， 治疗，可能是由于持续相对较高的甘油三酯（TG）水平。这突出表明， 新疗法靶向脂质代谢在心血管疾病的预防和治疗。基因组研究进展 编辑技术，特别是基础编辑器，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，如杜氏肌营养不良症（DMD）。在小鼠 在DMD模型中，我们最近在全身性治疗后实现了心脏中肌营养不良蛋白的几乎完全恢复。 腺相关病毒9（AAV 9）递送腺嘌呤碱基编辑器和gRNA。利用这个令人兴奋的 在体内基础编辑技术的进步，在这里，我们将开发更广泛适用的治疗 以“打了就跑”的方式（我们称之为diBE的技术）对抗CVD的策略，从而最大限度地减少 与已知的AAV介导的碱基编辑试剂的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。我们将确定二溴二苯醚的治疗潜力- 介导的Asgr 1沉默对高脂饮食诱导的高胆固醇血症的保护作用， 小鼠动脉粥样硬化。这些研究的完成将很有可能对《公约》的执行产生重大影响。 开发新的碱基编辑疗法来治疗高脂血症和CVD。