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:10313701
- 负责人:
- 金额:$ 71.73万
- 依托单位:
- 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:
- 关键词:AddressAnimal ModelAnimalsAntibodiesAromataseAtherosclerosisAwardCRISPR/Cas technologyCardiovascular DiseasesCardiovascular systemCause of DeathCellsChemistryCholesterolClinical TreatmentClinical TrialsCombined Modality TherapyCoronaryCoronary ArteriosclerosisDNADNA Double Strand BreakDangerousnessDependovirusDevelopmentDietDiseaseDrug TargetingDyslipidemiasElementsEngineeringEnzymesEvaluationEventFrequenciesGenesGeneticGenomeHepatocyteHigh Density LipoproteinsHigh Fat DietHumanHyperlipidemiaHypertriglyceridemiaIn VitroIncidenceKnock-outKnowledgeLDLR geneLipidsLongevityLow-Density LipoproteinsMediatingMeta-AnalysisMethodsModelingMonitorMusMutationNew ZealandNobel PrizeOryctolagus cuniculusPatientsPharmaceutical PreparationsPharmacologic SubstancePositioning AttributePre-Clinical ModelProteinsRNA InterferenceReportingResidual stateRiskSafetySagittariaStudy modelsTherapeuticTranscriptTriglyceridesTumorigenicityVariantVery low density lipoproteinWorkadeno-associated viral vectorapolipoprotein C-IIIatherogenesisatherosclerosis riskbasecardiovascular disorder preventioncardiovascular disorder riskcardiovascular disorder therapydensityefficacy evaluationexperimental studygene therapygenotoxicityhypercholesterolemiaimprovedin vivoinfancyinhibitor/antagonistinsightinteinknockout genelipid metabolismmouse modelnew therapeutic targetnovelnovel therapeuticsresponsetranslational 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,很大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(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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YUQING Eugene CHEN其他文献
YUQING Eugene CHEN的其他文献
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{{ truncateString('YUQING Eugene CHEN', 18)}}的其他基金
Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
- 批准号:
10580855 - 财政年份:2022
- 资助金额:
$ 71.73万 - 项目类别:
Browning of perivascular adipose tissue protects against thoracic aortic aneurysm
血管周围脂肪组织褐变可预防胸主动脉瘤
- 批准号:
10462357 - 财政年份:2022
- 资助金额:
$ 71.73万 - 项目类别:
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
- 批准号:
10652321 - 财政年份:2021
- 资助金额:
$ 71.73万 - 项目类别:
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
- 批准号:
10441548 - 财政年份:2021
- 资助金额:
$ 71.73万 - 项目类别:
IDOL and dyslipidemia in cardiovascular diseases
IDOL 与心血管疾病中的血脂异常
- 批准号:
10221773 - 财政年份:2019
- 资助金额:
$ 71.73万 - 项目类别:
IDOL and dyslipidemia in cardiovascular diseases
IDOL 与心血管疾病中的血脂异常
- 批准号:
10451711 - 财政年份:2019
- 资助金额:
$ 71.73万 - 项目类别:
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