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.

项目总结 心脏病是美国和世界范围内导致死亡的头号原因， 每年有超过655,000名美国人死亡。最常见的心血管疾病(CVD) 冠状动脉疾病(CAD)是复杂的遗传变异和环境因素相互作用的结果 各种因素。特别是，低密度脂蛋白(LDL)是动脉粥样硬化和 心血管疾病风险增加。他汀类药物的使用大大降低了心血管疾病的发生率。尽管 过去30年临床实践的巨大进步，低密度脂蛋白降胆固醇不足和相对 无论联合或不联合使用他汀类药物，相当大比例的患者仍有较高的残留风险 治疗，可能是由于持续相对较高的甘油三酯(TG)水平。这突显了需要额外的 针对脂代谢的新疗法在心血管疾病防治中的作用。基因组研究的最新进展 编辑技术，特别是基础编辑，使我们能够探索精确更正的可行性 遗传性心肌病的基因突变，如杜氏肌营养不良症(DMD)。在一只老鼠身上 DMD模型，我们最近在心脏实现了Dstrophin的近乎完全的恢复 腺嘌呤碱基编辑和腺相关病毒9(AAV9)的gRNA的传递。利用这一令人兴奋的 体内碱基编辑技术的进展，在这里我们将开发更广泛适用的治疗方法 以“肇事逃逸”的方式对抗心血管疾病的策略(我们称之为diBE技术)，从而最大限度地减少 已知的与AAV介导的碱基编辑试剂持续表达相关的潜在风险 具有固有的脱靶DNA和RNA编辑活动。我们将确定diBE的治疗潜力- Asgr1介导的沉默对高脂饮食诱导的高胆固醇血症的保护作用 小鼠的动脉粥样硬化。这些研究的完成将极有可能对 治疗高脂血症和心血管疾病的新型碱基编辑疗法的开发。