Development of gene editing based therapy for cardiovascular diseases

开发基于基因编辑的心血管疾病疗法

基本信息

批准号：
10652321
负责人：
YUQING Eugene CHEN
金额：
$ 70.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/10652321
关键词：
Address Animal Model Animals Antibodies Aromatase Atherosclerosis Award CRISPR/Cas technology Cardiovascular Diseases Cause of Death Cells Chemistry Cholesterol Clinical Treatment Clinical Trials Combined Modality Therapy Coronary Arteriosclerosis DNA DNA Double Strand Break Dangerousness Dependovirus Development Diet Disease Drug Targeting Dyslipidemias Elements Engineering Enzymes Evaluation Event Frequencies Genes Genetic Genome Germ Cells Hepatocyte High Density Lipoproteins High Fat Diet Human Hyperlipidemia Hypertriglyceridemia In Vitro Incidence Knock-out Knowledge LDLR gene Lipids Lipoproteins Longevity Mediating Meta-Analysis Methods Modeling Monitor Mus Mutation New Zealand Nobel Prize Oryctolagus cuniculus Patients Pharmaceutical Preparations Pharmacologic Substance Positioning Attribute Pre-Clinical Model Protein Splicing Proteins RNA Interference Reporting Residual state Risk Safety Sagittaria Study models Therapeutic Transcript Triglycerides Tumorigenicity Variant Very low density lipoprotein Work adeno-associated viral vector apolipoprotein C-III atherogenesis base editing base editor cardiovascular disorder prevention cardiovascular disorder risk cardiovascular disorder therapy cardiovascular risk factor coronary event density efficacy evaluation experimental study gene therapy genotoxicity hypercholesterolemia improved in vivo infancy inhibitor insight intein knockout gene lipid metabolism mouse model new therapeutic target novel novel therapeutics response translational study

项目摘要

PROJECT SUMMARY/ABSTRACT Recent therapeutic advances considerably reduced the incidence of cardiovascular disease (CVD). The contribution of low-density (LDL) and very low density (VLDL) lipoproteins is critical in atherogenesis. Regardless the progress of clinical treatments in the past 30 years, for a significant proportion of statin-treated patients, with or without combination therapy, insufficient LDL-C reduction and relatively high residual risk still remain, likely associated with persistent relatively high triglyceride (TG) levels, thus limiting the benefits of these therapies. This underscores the need for additional new therapies targeting lipid metabolism in CVD prevention and treatment. In this proposal, we propose to develop genetic deficiency of ApoC3 through an adeno-associated virus (AAV) mediated in vivo silencing of ApoC3 by Cas9 base editor (Cas9-BE) strategy (AAV-Cas9-BE-ApoC3) to render protection against high cholesterol diet-induced hypercholesterolemia and atherosclerosis in rabbits. Specifically, we will 1) develop AAV-Cas9-BE-ApoC3 in a preclinical model species, the New Zealand White rabbits. We will determine the optimal targeting strategies using in vitro cultured rabbit cells, followed by experiments to determine the optimal delivery parameters to achieve effective ApoC3 gene knockout in rabbit hepatocytes; 2) evaluate the efficacy of AAV-Cas9-BE-ApoC3 using optimal conditions determined in Aim 1 to knockout ApoC3 in rabbits; 3) conduct multiple-year evaluation of the safety of AAV- Cas9-BE-ApoC3 in rabbits. Completion of these aims by leveraging new CRISPR/Cas9 technology to target ApoC3 will provide compelling evidence to establish ApoC3 as a novel feasible target for gene editing-based therapy for hyperlipidemia and CVD.

项目概要/摘要最近的治疗进展大大降低了心血管疾病（CVD）的发病率。这低密度（LDL）和极低密度（VLDL）脂蛋白的作用在动脉粥样硬化形成中至关重要。无论过去30年临床治疗取得怎样的进展，相当一部分接受他汀类药物治疗的患者患者，无论是否接受联合治疗，LDL-C降低不足且残留风险仍然较高仍然存在，可能与持续相对较高的甘油三酯（TG）水平有关，从而限制了这些疗法。这强调需要针对 CVD 脂质代谢的其他新疗法预防和治疗。在本提案中，我们建议通过开发 ApoC3 的遗传缺陷通过 Cas9 碱基编辑器 (Cas9-BE) 策略，腺相关病毒 (AAV) 介导 ApoC3 体内沉默 (AAV-Cas9-BE-ApoC3) 提供保护，防止高胆固醇饮食引起的高胆固醇血症和兔子的动脉粥样硬化。具体来说，我们将 1) 在临床前模型物种中开发 AAV-Cas9-BE-ApoC3，新西兰白兔。我们将利用体外培养的兔确定最佳靶向策略细胞，然后通过实验确定最佳递送参数以实现有效的 ApoC3 基因兔肝细胞的敲除； 2) 使用最佳条件评估AAV-Cas9-BE-ApoC3的功效目标 1 确定敲除兔子中的 ApoC3； 3）对AAV的安全性进行多年评估- 兔子体内的 Cas9-BE-ApoC3。通过利用新的 CRISPR/Cas9 技术来靶向完成这些目标 ApoC3 将提供令人信服的证据，将 ApoC3 确立为基于基因编辑的新型可行靶标治疗高脂血症和CVD。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

First in vivo base-editing trial shows promise.

首次体内碱基编辑试验显示出希望。

DOI：
发表时间：
2024-01-03
期刊：
影响因子：
0
作者：
Han; Renzhi
通讯作者：
Renzhi

Correction of DMD in human iPSC-derived cardiomyocytes by base-editing-induced exon skipping.

通过碱基编辑诱导的外显子跳跃校正人 iPSC 衍生的心肌细胞中的 DMD。

DOI：
发表时间：
2023-03-09
期刊：
影响因子：
0
作者：
Wang, Peipei;Li, Haiwen;Zhu, Mandi;Han, Rena Y;Guo, Shuliang;Han, Renzhi
通讯作者：
Han, Renzhi

The Versatile Biocatalyst of Cytochrome P450 CYP102A1: Structure, Function, and Engineering.

细胞色素 P450 CYP102A1 的多功能生物催化剂：结构、功能和工程。

DOI：
发表时间：
2023-07-12
期刊：
影响因子：
0
作者：
Sun, Yudong;Huang, Xiaoqiang;Osawa, Yoichi;Chen, Yuqing Eugene;Zhang, Haoming
通讯作者：
Zhang, Haoming

Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice.

通过 AAV 递送对 Angptl3 进行肝脏特异性体内碱基编辑可有效降低小鼠的血脂水平。

DOI：
发表时间：
2023-06-15
期刊：
影响因子：
0
作者：
Zuo, Yuanbojiao;Zhang, Chen;Zhou, Yuan;Li, Haiwen;Xiao, Weidong;Herzog, Roland W;Xu, Jie;Zhang, Jifeng;Chen, Y Eugene;Han, Renzhi
通讯作者：
Han, Renzhi

Decoding CRISPR-Cas PAM recognition with UniDesign.

使用 UniDesign 解码 CRISPR-Cas PAM 识别。