Base editing of ASGR1 for cardiovascular disease
ASGR1 碱基编辑治疗心血管疾病
基本信息
- 批准号:10590146
- 负责人:
- 金额:$ 19.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:ANGPTL3 geneAdenineAmericanArterial Fatty StreakAtherosclerosisBenchmarkingBiochemicalCardiovascular DiseasesCardiovascular systemCause of DeathCellsCessation of lifeCholesterolClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyCommunicationComplexConsumptionCoronary ArteriosclerosisCoronary OcclusionsCoronary heart diseaseDNADNA Double Strand BreakDNA Sequence AlterationDangerousnessDependovirusDevelopmentDietary FatsDiseaseDuchenne muscular dystrophyDyslipidemiasDystrophinEnvironmental Risk FactorEnzyme-Linked Immunosorbent AssayEventGenesGenomic DNAGuide RNAHeartHeart DiseasesHigh Density LipoproteinsHigh Fat DietHistologicHyperlipidemiaHypertriglyceridemiaImmune responseIncidenceKnockout MiceLDL Cholesterol LipoproteinsLesionLightLipidsLiverLow-Density LipoproteinsMeasurementMediatingMedicineMolecularMusMutationMyocardial InfarctionNatureNonsense MutationOrganPatientsPharmaceutical PreparationsPhysiologicalPlasmaPoint MutationPublishingRNARNA EditingReagentResidual stateRiskRisk FactorsRoleRunningSafetySerologySpecificityStainsSystemT-LymphocyteTechnologyTestingTherapeuticTherapeutic EffectUnited StatesViral Packagingbase editingbase editorcardiovascular disorder preventioncardiovascular disorder riskclinical practicecombatcoronary artery occlusiondeep sequencingdesignempowermentgenetic approachgenetic variantgenome editinggenome wide association studyheart disease riskhypercholesterolemiaimprovedin vivoinherited cardiomyopathyinhibitorlipid metabolismloss of function mutationmouse modelnew therapeutic targetnovelnovel therapeuticspreventresearch and developmentrestorationtechnology platformtherapeutic developmenttherapeutic genome editingtranscriptometranscriptome sequencingtranscriptomicstumorigenic
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Renzhi Han', 18)}}的其他基金
Myokine function of MG53 in muscle injury-repair and regeneration
MG53在肌肉损伤修复和再生中的肌因子功能
- 批准号:
10268967 - 财政年份:2017
- 资助金额:
$ 19.81万 - 项目类别:
Molecular and cellular functions of Ano5 in heart
Ano5在心脏中的分子和细胞功能
- 批准号:
8823821 - 财政年份:2015
- 资助金额:
$ 19.81万 - 项目类别:
Molecular and cellular functions of Ano5 in heart
Ano5在心脏中的分子和细胞功能
- 批准号:
9035423 - 财政年份:2015
- 资助金额:
$ 19.81万 - 项目类别:
Molecular and cellular functions of Ano5 in heart
Ano5在心脏中的分子和细胞功能
- 批准号:
8981124 - 财政年份:2015
- 资助金额:
$ 19.81万 - 项目类别:
Mechanisms of Muscle Inflammation in Muscular Dystrophy
肌营养不良症中肌肉炎症的机制
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9271865 - 财政年份:2014
- 资助金额:
$ 19.81万 - 项目类别:
Mechanisms of Muscle Inflammation in Muscular Dystrophy
肌营养不良症中肌肉炎症的机制
- 批准号:
8847225 - 财政年份:2014
- 资助金额:
$ 19.81万 - 项目类别:
Molecular and cellular functions of Ano5 in heart
Ano5在心脏中的分子和细胞功能
- 批准号:
8690963 - 财政年份:2013
- 资助金额:
$ 19.81万 - 项目类别:
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