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。
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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Renzhi Han其他文献
Renzhi Han的其他文献
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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
- 批准号:
8847225 - 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:
9271865 - 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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