CRISPR/Cas基因编辑技术在心血管疾病中的应用研究进展

doi:10.3969/j.issn.1674-8115.2026.03.010

摘要/Abstract

摘要：

基因编辑技术可对生物体基因组或转录产物进行定点修饰。10余年来，以CRISPR/Cas9为代表的新一代基因编辑技术迅速发展，在效率、安全性和应用广度方面均优于传统锌指核酸酶（zinc finger nuclease，ZFN）和转录激活因子样效应物核酸酶（transcription activator-like effector nuclease，TALEN）技术，逐步从实验室研究走向临床转化阶段。心血管疾病是全球死亡和健康损害的主要原因之一，现有治疗手段常面临靶点难成药、副作用大及疗效有限等挑战。对于部分传统药物治疗无效的心血管疾病病例，基因编辑技术提供了新的治疗思路。目前，该技术已应用于针对转甲状腺素蛋白淀粉样变、高脂血症等疾病的药物开发，其中NTLA-2001和CTX310等药物已率先进入临床试验阶段。降低免疫反应与脱靶风险、突破心脏靶向递送瓶颈，是该技术实现临床转化的关键。随着人工智能辅助设计与非病毒载体等新技术的成熟，CRISPR/Cas技术有望突破当前的肝脏靶向限制，实现心脏原位治疗，为心血管疾病提供更具根治潜力的治疗策略。该文系统梳理CRISPR/Cas系统的结构与作用机制，总结近年来其在心血管疾病中的应用进展，包括基因敲除、表观编辑、碱基编辑、先导编辑及RNA编辑等多个方向，以期为该领域的后续研究与临床转化提供参考。

关键词: 基因编辑, 心血管疾病, CRISPR/Cas

Abstract:

Gene editing technologies refer to a class of techniques capable of precisely modifying or manipulating the genome or transcriptome of living organisms. Over the past decade, next-generation gene editing tools, represented by CRISPR/Cas9, have rapidly advanced, demonstrating superior efficiency, safety, and broader applicability compared to traditional methods, such as zinc finger nuclease (ZFN) and transcription activator-like effector nuclease (TALEN). These advancements have facilitated the transition of gene editing from basic research to clinical applications. Cardiovascular diseases remain a leading cause of global mortality and health burden, yet current treatments face challenges such as undruggable targets, significant side effects, and limited efficacy. For certain conditions that are difficult to treat with conventional pharmacotherapy, gene editing offers a novel therapeutic approach. Currently, this technology has been successfully applied to drug development for diseases such as transthyretin amyloidosis and hyperlipidemia, with pioneering candidates such as NTLA-2001 and CTX310 having entered clinical trials. Mitigating immune responses and off-target effects, along with overcoming cardiac-targeted delivery barriers, are pivotal for clinical translation. With advancements in artificial intelligence-assisted design and non-viral vectors, CRISPR/Cas technology is expected to overcome current liver-predominant limitations, paving the way for in situ cardiac treatment and offering a curative strategy for cardiovascular diseases. This article systematically reviews the structure and mechanism of CRISPR/Cas systems and summarizes recent advances in their applications to cardiovascular diseases, including gene knockout, epigenetic editing, base editing, prime editing, and RNA editing, aiming to provide important references for subsequent research and clinical translation in this field.

Key words: gene editing, cardiovascular disease, CRISPR/Cas

中图分类号:

田启嘉, 贾康妮, 闫小响. CRISPR/Cas基因编辑技术在心血管疾病中的应用研究进展[J]. 上海交通大学学报（医学版）, 2026, 46(3): 358-367.

Tian Qijia, Jia Kangni, Yan Xiaoxiang. Advances in CRISPR/Cas gene editing and its applications in cardiovascular diseases[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2026, 46(3): 358-367.

图/表 2

参考文献 76

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Treatment	Gene editing method	Indication	Target gene	Delivery method	Clinical trial ID	Phase	Efficacy	Follow-up	Safety	Reference
NTLA-2001	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	NCT06128629	Ⅲ	TTR reduction: 89% (Day 28), 90% (Month 12)	87% reduction sustained (Month 36)	Most common treatment-related AEs: mild infusion-related reactions (14%) and transient liver enzyme elevations (6%)	[6-7]
YOLT-201	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	NCT06539208	Ⅰ/Ⅱa	Trial ongoing	\	\	[38]
ART001	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	ChiCTR2400081216	Ⅰ	Trial ongoing	\	\	[39]
YOLT-101	Base editing	Familial hypercholesterolemia	PCSK9	GalNAc-LNP	NCT06458010	Ⅰ	High-dose (0.6 mg/kg): PCSK9 reduced by 72.5% and LDL-C by 50.4% (Month 4)	Follow-up ongoing	Most common treatment-related AEs; mild infusion-related reactions (83%) and transient liver enzyme elevations (50%)	[40]
VERVE-101	Base editing	Familial hypercholesterolemia	PCSK9	LNP	NCT05398029	Ⅰ	High-dose (0.6 mg/kg): PCSK9 reduced by 47% and LDL-C by 55% (Day 28); sustained through 180 d	Follow-up ongoing	Treatment-related Grade 3 serious AEs: transient liver enzyme elevations and thrombocytopenia; mild infusion-related reactions were common; trial enrollment paused due to safety concerns	[25]
VERVE-102	Base editing	Familial hypercholesterolemia or premature coronary artery disease	PCSK9	GalNAc-LNP	NCT06164730	Ⅰ	Trial ongoing	\	\	[41]
CTX320	CRISPR/Cas9 knock out	Atherosclerosis or calcific aortic valve stenosis	LPA	LNP	ACTRN12623001095651	Ⅰ	Trial ongoing	\	\	[42]
CTX310	CRISPR/Cas9 knock out	Refractory dyslipidemias	ANGPTL3	LNP	ACTRN12623000809639	Ⅰ	High-dose (0.8 mg/kg): ANGPTL3 reduced by 73.2%, LDL-C by 48.9%, and triglycerides by 55.2% (Day 60)	Follow-up ongoing	Most common treatment-related AEs: mild infusion-related reactions (20%) and transient liver enzyme elevations (7%)	[9]
VERVE-201	Base editing	Refractory hypercholesterolemia	ANGPTL3	GalNAc-LNP	NCT06451770	Ⅰ	Trial ongoing	\	\	[43]

Treatment	Gene editing method	Indication	Target gene	Delivery method	Clinical trial ID	Phase	Efficacy	Follow-up	Safety	Reference
NTLA-2001	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	NCT06128629	Ⅲ	TTR reduction: 89% (Day 28), 90% (Month 12)	87% reduction sustained (Month 36)	Most common treatment-related AEs: mild infusion-related reactions (14%) and transient liver enzyme elevations (6%)	[6-7]
YOLT-201	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	NCT06539208	Ⅰ/Ⅱa	Trial ongoing	\	\	[38]
ART001	CRISPR/Cas9 knock out	ATTR-CM	TTR	LNP	ChiCTR2400081216	Ⅰ	Trial ongoing	\	\	[39]
YOLT-101	Base editing	Familial hypercholesterolemia	PCSK9	GalNAc-LNP	NCT06458010	Ⅰ	High-dose (0.6 mg/kg): PCSK9 reduced by 72.5% and LDL-C by 50.4% (Month 4)	Follow-up ongoing	Most common treatment-related AEs; mild infusion-related reactions (83%) and transient liver enzyme elevations (50%)	[40]
VERVE-101	Base editing	Familial hypercholesterolemia	PCSK9	LNP	NCT05398029	Ⅰ	High-dose (0.6 mg/kg): PCSK9 reduced by 47% and LDL-C by 55% (Day 28); sustained through 180 d	Follow-up ongoing	Treatment-related Grade 3 serious AEs: transient liver enzyme elevations and thrombocytopenia; mild infusion-related reactions were common; trial enrollment paused due to safety concerns	[25]
VERVE-102	Base editing	Familial hypercholesterolemia or premature coronary artery disease	PCSK9	GalNAc-LNP	NCT06164730	Ⅰ	Trial ongoing	\	\	[41]
CTX320	CRISPR/Cas9 knock out	Atherosclerosis or calcific aortic valve stenosis	LPA	LNP	ACTRN12623001095651	Ⅰ	Trial ongoing	\	\	[42]
CTX310	CRISPR/Cas9 knock out	Refractory dyslipidemias	ANGPTL3	LNP	ACTRN12623000809639	Ⅰ	High-dose (0.8 mg/kg): ANGPTL3 reduced by 73.2%, LDL-C by 48.9%, and triglycerides by 55.2% (Day 60)	Follow-up ongoing	Most common treatment-related AEs: mild infusion-related reactions (20%) and transient liver enzyme elevations (7%)	[9]
VERVE-201	Base editing	Refractory hypercholesterolemia	ANGPTL3	GalNAc-LNP	NCT06451770	Ⅰ	Trial ongoing	\	\	[43]