Gene Therapy in Hutchinson-Gilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症的基因治疗
基本信息
- 批准号:10343225
- 负责人:
- 金额:$ 74.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-15 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:2 year old5 year oldAddressAdenineAdolescentAdultAgeAge-MonthsAgingAnimalsAortaAtherosclerosisAutomobile DrivingBase PairingBenchmarkingBiomedical ResearchBirthBlood VesselsCell CountCell DeathCellsCessation of lifeChildClinical TrialsClonalityDNADNA DamageDNA strand breakDataDefectDependovirusDiseaseDominant-Negative MutationDoseEndothelial CellsFibroblastsFibrosisFutureGenesGeneticGenetic DiseasesGenomeHealthHepaticHumanImmune responseInjectionsLamin Type ALeadLeukocytesMeasuresMessenger RNAMissionModelingMolecularMultiple Organ FailureMusMutationNatureNewly DiagnosedNucleotidesOutcomeParacrine CommunicationPathogenicityPathologyPatientsPhenotypePoint MutationPopulationPre-Clinical ModelPreventionProductionProgeriaProliferatingProteinsPublic HealthPublishingRNA EditingRNA SplicingRecoveryResearchSalineSmooth Muscle MyocytesSyndromeTechniquesTestingTherapeuticTimeTissuesTranslatingUnited States National Institutes of HealthValidationVascular DiseasesVascular Smooth MuscleWorkbasebase editingbase editorburden of illnesscausal variantcohortcurative treatmentsdisabilitydisease phenotypegene therapyhuman diseasehumanized mouseimprovedinnovationjuvenile animalmature animalmortalitymouse modelmutantpreclinical efficacyprematurepreventprogramsprotein expressionsenescencesingle-cell RNA sequencingtime usetreatment strategytumorigenesisvascular smooth muscle cell proliferation
项目摘要
Project Summary and Abstract
Hutchinson-Gilford Progeria Syndrome (HGPS) is an incurable, uniformly fatal disease involving a point mutation
in a gene called Lamin A (LMNA). Children develop signs of HGPS typically within the two years after birth and
die at a median age of 14, most commonly from progressive atherosclerotic cardiovascular disease. Although
the causal mutation in HGPS was identified 18 years ago, no cures for this disease exist. Programmable base
editing of DNA now enables the previously unprecedented ability to change single nucleotides in DNA and correct
pathogenic mutations with DNA strand breaks. HGPS represents a tractable disease to test base editing,
however it remains completely unknown whether this strategy will improve disease phenotypes associated with
HGPS. As such, there is a critical need to study how DNA base editing alters the molecular defects driving HGPS
in order to determine whether this genome therapy can fulfill its promise to cure disease. Our overall objective
in this proposal is develop adenine base editing (ABE) as a treatment strategy for HGPS. Our central hypothesis
is that ABE-treatment of adult mice can achieve sufficient editing in aortas to reverse vascular pathology through
cell-autonomous effects on survival and clonal proliferation in VSMCs. Our hypothesis is formulated based on
newly published and new preliminary data that demonstrate: 1) scarless correction of the pathogenic mutation
by ABE in patient fibroblasts and in a humanized mouse model of HGPS; 2) prevention of vascular pathology
and recovery of VSMCs at 6 months after ABE treatment of juvenile mice; 3) a significant increase in overall
survival of ABE-treated juvenile animals. The rationale for this project is that validation of base editing therapies
is needed to determine their potential in treating systemic human diseases. To attain our objectives, we will
pursue the following two specific aims: 1) Test whether DNA editing improves vascular pathology in established
disease by treating adult HGPS animals at different ages with a single injection of AAV-ABE; 2) Identify the
mechanism(s) promoting VSMC recovery after ABE treatment. The overall contribution of this work will be to
elucidate how adenine DNA base editing improves phenotypes in HGPS. The central innovation of this proposal
is a conceptual shift in therapeutic treatment of HGPs by focusing on correcting the underlying pathogenic
mutation in cells and tissues.
项目概要和摘要
Hutchinson-Gilford早衰综合征(HGPS)是一种涉及点突变的无法治愈的致命疾病
一种叫做核纤层蛋白A(LMNA)的基因。儿童通常在出生后两年内出现HGPS的迹象,
死亡的中位年龄为14岁,最常见于进行性动脉粥样硬化性心血管疾病。虽然
HGPS的致病突变是在18年前发现的,但目前还没有治愈这种疾病的方法。可编程基
DNA的编辑现在使以前前所未有的能力改变DNA中的单个核苷酸,
DNA链断裂的致病性突变。HGPS代表了一种易于测试碱基编辑的疾病,
然而,这种策略是否会改善与以下疾病相关的疾病表型仍然完全未知:
HGPS因此,迫切需要研究DNA碱基编辑如何改变驱动HGPS的分子缺陷
以确定这种基因组疗法是否能够实现其治愈疾病的承诺。我们的整体目标
在该建议中,开发了腺嘌呤碱基编辑(ABE)作为HGPS治疗策略。我们的核心假设
成年小鼠的ABE治疗可以通过以下方式在动脉瘤中实现足够的编辑以逆转血管病理学:
细胞自主性对VSMCs存活和克隆增殖的影响。我们的假设是基于
新发表的和新的初步数据表明:1)致病突变的无瘢痕校正
通过ABE在患者成纤维细胞和HGPS的人源化小鼠模型中的作用; 2)预防血管病理学
在幼年小鼠ABE治疗后6个月,VSMCs的恢复; 3)总体上,
ABE处理的幼龄动物的存活率。该项目的基本原理是,
以确定它们在治疗系统性人类疾病中的潜力。为了实现我们的目标,我们将
追求以下两个具体目标:1)测试DNA编辑是否改善了已建立的血管病理学。
通过用AAV-ABE的单次注射治疗不同年龄的成年HGPS动物来治疗疾病; 2)鉴定HGPS动物的免疫原性;
ABE治疗后促进VSMC恢复的机制。这项工作的总体贡献将是
阐明腺嘌呤DNA碱基编辑如何改善HGPS的表型。该提案的核心创新之处在于
是HGP治疗的概念转变,其重点是纠正潜在的致病性
细胞和组织中的突变。
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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JONATHAN David BROWN其他文献
JONATHAN David BROWN的其他文献
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{{ truncateString('JONATHAN David BROWN', 18)}}的其他基金
Gene Therapy in Hutchinson-Gilford Progeria Syndrome
哈钦森-吉尔福德早衰综合症的基因治疗
- 批准号:
10583487 - 财政年份:2022
- 资助金额:
$ 74.24万 - 项目类别:
Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
- 批准号:
10586037 - 财政年份:2020
- 资助金额:
$ 74.24万 - 项目类别:
Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
- 批准号:
9974212 - 财政年份:2020
- 资助金额:
$ 74.24万 - 项目类别:
Elucidating the chromatin-dependent mechanisms governing chronic inflammatory activation of endothelial cells in atherosclerosis.
阐明控制动脉粥样硬化中内皮细胞慢性炎症激活的染色质依赖性机制。
- 批准号:
10363671 - 财政年份:2020
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8197786 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8029238 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
9275086 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8586546 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
9121837 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
Hepatic Lipase, PPAR-delta and Fatty Acid Metabolism
肝脂肪酶、PPAR-δ 和脂肪酸代谢
- 批准号:
8388774 - 财政年份:2010
- 资助金额:
$ 74.24万 - 项目类别:
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