CRISPR gene therapies targeting tau in Alzheimer's disease and tauopathies
针对阿尔茨海默病和 tau 病中 tau 蛋白的 CRISPR 基因疗法
基本信息
- 批准号:10752745
- 负责人:
- 金额:$ 42.41万
- 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:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:Alzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAlzheimer&aposs disease therapeuticAntisense OligonucleotidesBiochemicalBrainCRISPR/Cas technologyCell LineClustered Regularly Interspaced Short Palindromic RepeatsCognitiveComplexDNADNA DamageDataDefectDementiaDevelopmentDiseaseDisease ProgressionEffectivenessEpitopesFlowersFunctional disorderGenomeGenomic DNAGoalsGuide RNAHumanHuman Cell LineImmunotherapyImpaired cognitionIn VitroInjectionsLentivirusLibrariesMAPT geneMeasuresMediatingMemory LossMethodsModalityModelingMusNerve DegenerationNervous SystemNeuronsOnset of illnessPathologyPatientsPenetrancePenetrationPeripheralPick Disease of the BrainProgressive Supranuclear PalsyPropertyProtein IsoformsRNASerotypingSiteSpecificitySynapsesSystemTauopathiesTechnologyTestingTherapeuticTimeTranscriptValidationVariantbehavioral studychemical stabilitycorticobasal syndromeefficacy testinggene therapyhistological studiesimprovedin vivoinnovationinterestintravenous injectionknock-downmouse modelmulti-electrode arraysnovelpreclinical efficacytargeted treatmenttau Proteinstau aggregationtherapeutic evaluationtooltumorigenesis
项目摘要
PROJECT SUMMARY / ABSTRACT
The MAPT gene encoding the tau protein is an ideal target for Alzheimer’s disease (AD) therapeutics since it
forms hallmark pathology in all AD patients. In mice, tau aggregation drives disease progression, while
depleting tau leads to cognitive improvements, suggesting targeting tau may benefit human patients as well. A
major question has been how to achieve this goal. CRISPR technology (Clustered Regularly Interspaced Short
Palindromic Repeats) has blossomed in recent years, and we can now leverage this approach to specifically
deplete tau in neurons. By targeting different tau isoforms with site-specific guide RNAs of interest, one can
conceivably target the specific tau variants that are present in 3R-tauopathies (e.g., Pick’s disease), 4R
tauopathies (e.g., corticobasal syndrome), or mixed 3R/4R tauopathies (e.g., AD patients). Thus, we turned to
a newly developed CRISPR/Cas13 technology, which allows targeting and depletion of RNA transcripts rather
than DNA itself, the latter of which can have unwanted effects on the genome including DNA damage and even
tumorigenesis. CRISPR/Cas13 technology could provide new opportunities for therapeutic tau reduction and
potentially overcome many of the limitations that have plagued tau depletion strategies. In fact, our preliminary
findings show that we can computationally predict which guides will successfully target and deplete tau, and
we demonstrated this in a human cell line and primary human neurons, suggesting we have found an optimal
pipeline for guide prediction, development, and validation. Therefore, we have an exciting opportunity to
develop an effective, non-invasive tool for tau gene therapy in the nervous system (CNS). In Aim-1, we will
develop and refine the CRISPR/Cas13 system to target tau and will comprehensively identify the most optimal
guide RNAs that target either 3R-tau, 4R-tau, or total tau. We will deliver those guides to neurons and
determine their effectiveness and ability to restore normal neuronal function. In Aim-2, we will perform
preclinical efficacy testing and determine whether our most optimal CRISPR/Cas13 complexes have
therapeutic potential in AD model mice. By delivering tau-targeting guides peripherally using brain-penetrant
AAV methods, we will evaluate their therapeutic impact by performing a battery of biochemical, histological,
and behavioral studies at either early (preventative) or late (therapeutic) stages of disease progression. This
study is innovative and significant since it will both develop the CRISPR technology needed to target tau, and
also advance gene therapy approaches to deplete tau in humans including AD and other dementia patients.
The clear implications are that targeting and reducing tau levels, even modestly, could provide a new treatment
modality for dementia patients.
项目摘要/摘要
项目成果
期刊论文数量(0)
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Todd Jonathan Cohen其他文献
Todd Jonathan Cohen的其他文献
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{{ truncateString('Todd Jonathan Cohen', 18)}}的其他基金
Identifying kinase signaling pathways linked to tau-mediated neurodegeneration
识别与 tau 介导的神经变性相关的激酶信号通路
- 批准号:
10753257 - 财政年份:2023
- 资助金额:
$ 42.41万 - 项目类别:
Sleep-dependent synaptic homeostasis in Alzheimer's disease
阿尔茨海默病中睡眠依赖性突触稳态
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10209327 - 财政年份:2021
- 资助金额:
$ 42.41万 - 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
- 批准号:
10382389 - 财政年份:2020
- 资助金额:
$ 42.41万 - 项目类别:
Identifying Alzheimer’s Disease Causal Variants and Target Genes Using iPSC-derived Microglia
使用 iPSC 衍生的小胶质细胞识别阿尔茨海默病致病变异和靶基因
- 批准号:
10615602 - 财政年份:2020
- 资助金额:
$ 42.41万 - 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
- 批准号:
10088361 - 财政年份:2019
- 资助金额:
$ 42.41万 - 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
- 批准号:
10319914 - 财政年份:2019
- 资助金额:
$ 42.41万 - 项目类别:
Dual CHIP Functions Control Tau Triage In Alzheimer's Disease
双芯片功能控制阿尔茨海默氏病的 Tau 分类
- 批准号:
10539271 - 财政年份:2019
- 资助金额:
$ 42.41万 - 项目类别:
Elucidating The Aberrant TDP-43 Species That Promote Neurodegeneration
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10385722 - 财政年份:2018
- 资助金额:
$ 42.41万 - 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
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- 批准号:
8849550 - 财政年份:2014
- 资助金额:
$ 42.41万 - 项目类别:
TDP-43 acetylation as a pathogenic modification in ALS & related proteinopathies
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- 批准号:
8862550 - 财政年份:2014
- 资助金额:
$ 42.41万 - 项目类别:
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