Testing Optimal Gene Editor for an Alzheimer's CRISPR therapeutic.
测试阿尔茨海默病 CRISPR 疗法的最佳基因编辑器。
基本信息
- 批准号:10746716
- 负责人:
- 金额:$ 211.28万
- 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 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Advisory CommitteesAlzheimer&aposs DiseaseAlzheimer&aposs disease therapeuticAlzheimer&aposs disease therapyAmyloidAmyloid beta-ProteinAmyloid beta-Protein PrecursorAttenuatedBiological AssayBrainCRISPR therapeuticsCRISPR/Cas technologyCell surfaceCellsClinicClinicalClinical PathsClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsConsensusConsultationsDepositionDiseaseDoseDown SyndromeEarly Onset Alzheimer DiseaseEndosomesEquilibriumEtiologyEventExonsEye diseasesFDA approvedFailureFutureGene ProteinsGenesGeneticGenomeGoalsGuide RNAHandHumanHuman Amyloid Precursor ProteinHuman GeneticsInjectionsKineticsKnock-inKnock-in MouseLeadLettersMeasuresMediatingMissionModalityMouse ProteinMusNerve RegenerationNeurofibrillary TanglesNeuronsOrganoidsOutcomePathologicPathway interactionsPersonsPharmaceutical PreparationsPhase I/II TrialPhysiologicalPhysiologyPositioning AttributeProtein CProtein FragmentProtein TruncationProteinsProteolysisPublic HealthQuantitative Reverse Transcriptase PCRRNARecommendationResearchResearch PersonnelRetinaRoleSafetySurfaceTestingTherapeuticTimeTranscriptTransmembrane DomainUnited States National Institutes of HealthVariantadeno-associated viral vectorbase editingbeta-site APP cleaving enzyme 1costefficacy testingexperimental studyextracellulargenome-widein vivoinduced pluripotent stem cellmeetingsmouse modelneuroprotectionnonhuman primatenovelnovel therapeuticspreventresponsesecretasetau Proteinstau aggregationtherapeutic genome editingtranslation to humans
项目摘要
Summary/Abstract:
The overall goal of this U01 proposal is to advance a unique CRISPR-based therapeutic for Alzheimer’s disease
(AD) towards the pre-IND stage, by determining the best genome-editor/gRNA combination that can be ultimately
used in clinical trials. Though there is an enormous unmet need for developing therapeutics for AD, we do not
have drugs that can unequivocally slow down the relentless course of AD. We have developed a gene-editing
based strategy targeting APP – a gene with a central and indisputable role in AD; strongly supported by human
genetics. We do not eliminate the APP gene, but edit out a pentapeptide YENPTY endocytic domain at the C-
terminus of APP, which blocks the entire pathologic APP β-cleavage pathway (including β-amyloid). The
transmembrane domain and the N-terminus remains intact, and the ∆C APP is retained on the cell surface,
leading to an increase in APP α-cleavage, which in turn upregulates neuroprotective and neuroregenerative APP
fragments. Thus, our strategy shifts the balance of APP cleavage from pathologic to physiologic, without
eliminating the gene. Since the targeted events are upstream, our strategy should be applicable to forms of AD
– sporadic and familial – and also to early-onset AD in Down syndrome, where APP triplication on Ch.21
invariably causes AD. So far, we have used the classical SaCas9 to demonstrate safety and efficacy of our
approach in vivo, but SaCas9 is too big to fit into a single AAV, which will be necessary for ultimate delivery in
humans. Moreover, since there is no FDA-approved gene-editing clinical trial in the brain yet, and the best
genome-editor is unknown. Here, we propose to first test two promising small genome-editors (and
corresponding gRNAs) that can fit into a single AAV – SaCas9 and NmCas9 – using genome-scale on- and off-
target assays (Aim 1). The best Lead-Editor/gRNA combinations emerging from these experiments will be tested
for efficacy, safety, predictability, and durability in human brain organoids and a novel APP mouse model where
the entire mouse APP was replaced with human APP (Aim 2). Collectively, these studies will not only clarify the
best genome-editor/RNA combination for editing the APP gene, but also help future trials in the brain gene-
editing space by determining the best editor for brain-relevant applications. Towards the end of our projects, we
propose to hold an INTERACT meeting with the FDA – in consultation with our Clinical/Translational Advisory
Team – to get regulatory input and consensus on pre-IND NHP studies. Upon completion, our studies will not
only offer a novel therapeutic in an arena of enormous unmet need and litany of failures, but also provide a
clinical path for future gene-editing efforts in this therapeutic space.
总结/摘要:
U 01提案的总体目标是推进一种独特的基于CRISPR的阿尔茨海默病治疗方法
(AD)通过确定最终可以实现的最佳基因组编辑器/gRNA组合,
用于临床试验。尽管开发AD治疗方法的需求巨大,但我们没有
有药物可以明确地减缓AD的无情进程。我们开发了一种基因编辑技术
基于靶向APP的策略-一种在AD中具有核心和无可争议的作用的基因;得到人类的强烈支持
遗传学我们没有消除APP基因,但编辑了一个五肽YENPTY内吞结构域在C-
APP末端,阻断整个病理性APP β-裂解途径(包括β-淀粉样蛋白)。的
跨膜结构域和N-末端保持完整,并且CD 4C APP保留在细胞表面上,
导致APP α裂解增加,进而上调神经保护和神经再生APP
片段因此,我们的策略将APP切割的平衡从病理性转移到生理性,
消除基因。由于目标事件是上游事件,我们的策略应适用于各种形式的广告
- 散发性和家族性-以及唐氏综合征中的早发性AD,其中第21章APP三倍
总是导致AD。到目前为止,我们已经使用经典的SaCas 9来证明我们的药物的安全性和有效性。
虽然SaCas 9在体内的方法是可行的,但SaCas 9太大而不能装入单个AAV,这对于最终递送到体内是必要的。
人类此外,由于目前还没有FDA批准的大脑基因编辑临床试验,
基因编辑器是未知的。在这里,我们建议首先测试两个有前途的小基因组编辑器(和
相应的gRNA),可以使用基因组规模的开启和关闭来适应单个腺相关病毒(SaCas 9和NmCas 9)
靶向测定(Aim 1)。将测试从这些实验中出现的最佳Lead-Editor/gRNA组合
在人脑类器官中的有效性、安全性、可预测性和耐久性,以及一种新型APP小鼠模型,
用人APP替换整个小鼠APP(Aim 2)。总的来说,这些研究不仅将澄清
最好的基因组编辑器/RNA组合编辑APP基因,但也有助于未来的大脑基因试验-
通过确定大脑相关应用程序的最佳编辑器来编辑空间。在项目结束时,我们
建议与FDA举行互动会议-与我们的临床/翻译顾问协商
团队-就IND前NHP研究获得监管意见和共识。完成后,我们的研究将不会
不仅在巨大的未满足需求和一连串失败的竞技场中提供了一种新的治疗方法,而且还提供了一种
为未来在这一治疗领域的基因编辑工作提供临床路径。
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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Subhojit Roy其他文献
Subhojit Roy的其他文献
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{{ truncateString('Subhojit Roy', 18)}}的其他基金
Pathophysiologic roles of alpha-synuclein at the synapse
α-突触核蛋白在突触中的病理生理作用
- 批准号:10330337 
- 财政年份:2021
- 资助金额:$ 211.28万 
- 项目类别:
Pathophysiologic roles of alpha-synuclein at the synapse
α-突触核蛋白在突触中的病理生理作用
- 批准号:9765861 
- 财政年份:2019
- 资助金额:$ 211.28万 
- 项目类别:
Pathophysiologic roles of alpha-synuclein at the synapse
α-突触核蛋白在突触中的病理生理作用
- 批准号:10164881 
- 财政年份:2019
- 资助金额:$ 211.28万 
- 项目类别:
Pathophysiologic roles of alpha-synuclein at the synapse
α-突触核蛋白在突触中的病理生理作用
- 批准号:10406165 
- 财政年份:2019
- 资助金额:$ 211.28万 
- 项目类别:
Pathophysiologic roles of alpha-synuclein at the synapse
α-突触核蛋白在突触中的病理生理作用
- 批准号:10617745 
- 财政年份:2019
- 资助金额:$ 211.28万 
- 项目类别:
A CRISPR-Cas9 screen to identify genetic modifiers of APP/BACE-1 interactions
用于鉴定 APP/BACE-1 相互作用的遗传修饰剂的 CRISPR-Cas9 筛选
- 批准号:9074668 
- 财政年份:2016
- 资助金额:$ 211.28万 
- 项目类别:
Trafficking and Endosomal Sorting of APP and BACE-1
APP 和 BACE-1 的运输和内体分选
- 批准号:9330505 
- 财政年份:2016
- 资助金额:$ 211.28万 
- 项目类别:
Trafficking and Endosomal Sorting of APP and BACE-1
APP 和 BACE-1 的运输和内体分选
- 批准号:9268509 
- 财政年份:2016
- 资助金额:$ 211.28万 
- 项目类别:
Trafficking and endosomal sorting of APP and BACE-1
APP 和 BACE-1 的运输和内体分选
- 批准号:8912971 
- 财政年份:2014
- 资助金额:$ 211.28万 
- 项目类别:
Trafficking and endosomal sorting of APP and BACE-1
APP 和 BACE-1 的运输和内体分选
- 批准号:8753904 
- 财政年份:2014
- 资助金额:$ 211.28万 
- 项目类别:

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