Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases
自噬:一种用于神经退行性疾病的自噬功能化基因治疗工具
基本信息
- 批准号:10888798
- 负责人:
- 金额:$ 45.71万
- 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 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease therapyAmyloid beta-ProteinAnimal ModelAnimalsArrhythmiaAutophagocytosisAutophagosomeBasic ScienceBrainBrain regionCause of DeathCell AggregationCellsChemicalsChimeric ProteinsClinical TrialsCognitiveCognitive deficitsDangerousnessDegradation PathwayDementiaDepositionDevelopmentDiseaseDisease modelDrug usageDyskinetic syndromeEngineeringExcisionExhibitsFoundationsFutureGenesGeneticGlutamatesHealthcareHippocampusHumanImpairmentIn VitroInjectionsKnock-inLearningLicensingMemory impairmentMotorMusMutationNamesNerve DegenerationNeurodegenerative DisordersNeuronsOrganoidsOutcomeParkinson DiseasePathogenesisPathogenicityPathway interactionsPatientsPeptidesPersonsPharmaceutical PreparationsPharmacotherapyPoly APopulationPrecision therapeuticsPreclinical TestingProcessProteinsPsychosesSpecificitySubstantia nigra structureSynapsesSynthetic GenesTestingTherapeuticTherapeutic EffectToxic effectVesicleViral Vectorabeta accumulationalpha synucleincare burdendelivery vehicledesigndrug candidateeffective therapyenhanced green fluorescent proteingene therapyin vivoinduced pluripotent stem cellinnovationmotor deficitmouse modelmutantneuroinflammationneuron lossneuronal survivalneurotoxicitynovelphosphoneuroprotein 14presenilin-1preventpromoterprotein aggregationreceptorrecruitreduce symptomsresearch clinical testingside effecttargeted treatmenttherapeutic evaluationtherapy developmenttool
项目摘要
Project Summary
Neurodegenerative diseases, especially Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), affect
millions of people globally and represent a US major healthcare burden. AD is the world’s most common cause
of dementia, and is the sixth leading cause of death in the US. PD is motor disabling condition that advances to
cognitive deficits. Currently there exist no effective therapies for AD or PD; even some of the drugs used to
ameliorate symptoms, such as in PD, cause serious long-term side effects that may be worse than the disease
itself. In AD and PD, accumulation of Amyloid-β (Aβ) or α-Synuclein (α-Syn) and their subsequent aggregation,
cause neuronal toxicity, including neuroinflammation, synaptic deficits and neurodegeneration, leading to
cognitive or motor deficits. In this application, we conceive an innovative genetic tool (named Autophagon, or
AFN) to be developed as a gene therapy that helps target toxic Aβ or α-Syn species to autophagy, an
important degradative pathway that is usually impaired in AD and PD. AFN will feature a synthetic gene
fragment to help sequester Aβ or α-Syn aggregates and deliver them to the autophagic vesicles for clearance
from the neurons. Using viral vectors, we will deliver AFN to cells or to mouse brain via specific stereotaxic
injections. First, we will test AFN in vitro using 2D and 3D (brain organoid) neuronal cultures derived from
iPSCs harboring APP/PSEN1 or α-Syn mutations that drive Aβ or α-Syn aggregation, respectively, and assess
the ability of AFN to suppress aggregate formation and neuronal toxicity. Second, we will use mouse models of
AD (with a genetic knock-in of human APP mutations that cause Aβ aggregation) and PD (expressing
aggregation-prone mutant human α-Syn) to test the therapeutic potential of AFN and its ability to prevent
aggregate formation, neurodegeneration, and cognitive or motor deficits in vivo. If successful, the proposed
project will have a major impact on the neurodegenerative diseases field, by developing an effective potential
gene therapy for AD and PD, and set the foundation for the next steps of preclinical and clinical testing of this
suggested therapy. It may also provide a proof-of-concept for therapy development for other
neurodegenerative disorders associated with protein aggregation.
项目摘要
神经退行性疾病,特别是阿尔茨海默病(AD)和帕金森病(PD),影响
全球有数百万人,是美国医疗保健的主要负担。广告是世界上最常见的事业
痴呆症,是美国第六大致死原因。帕金森病是一种进展到
认知缺陷。目前尚无有效的治疗AD或PD的方法;甚至一些用于治疗AD或PD的药物
改善症状,如帕金森病,会导致严重的长期副作用,可能比疾病更严重
它本身。在AD和PD中,淀粉样蛋白-β(A-β)或α-突触核蛋白(α-Syn)的积累及其随后的聚集,
引起神经元毒性,包括神经炎症、突触缺陷和神经变性,导致
认知或运动障碍。在本申请中,我们设想了一种创新的遗传工具(名为Autophagon,或
AFN)将被开发为一种基因疗法,有助于针对有毒的Aβ或α-Syn物种进行自噬,以及
在阿尔茨海默病和帕金森病中通常受损的重要降解途径。AFN将以合成基因为特色
帮助隔离Aβ或α-Syn聚集体的片段,并将它们运送到自噬小泡进行清除
来自神经元的。利用病毒载体,我们将通过特定的立体定位将AFN传递到细胞或小鼠的大脑
打针。首先,我们将使用2D和3D(脑器官)神经元培养物在体外测试AFN。
携带APP/PSEN1或α-SYN突变的IPSC分别驱动Aβ或α-SYN聚集,并评估
AFN抑制聚集形成和神经元毒性的能力。其次,我们将使用
AD(具有导致Aβ聚集的人类APP突变的基因敲入)和PD(表达
容易聚集的突变体人α-Syn)来测试黄曲霉毒素的治疗潜力及其预防能力
体内的聚集体形成、神经变性和认知或运动障碍。如果成功,建议的
该项目将通过开发有效的潜力,对神经退行性疾病领域产生重大影响
AD和PD的基因治疗,并为下一步的临床前和临床测试奠定了基础
建议的治疗方法。它还可以为其他疾病的治疗开发提供概念验证
与蛋白质聚集相关的神经退行性疾病。
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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Abraam M. Yakoub其他文献
Brain organoids: building higher-order complexity and neural circuitry models
脑类器官:构建高阶复杂性和神经回路模型
- DOI:
10.1016/j.tibtech.2025.02.009 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:14.900
- 作者:
Gulimiheranmu Maisumu;Stephanie Willerth;Michael W. Nestor;Ben Waldau;Stefan Schülke;Francesco V. Nardi;Osama Ahmed;You Zhou;Madel Durens;Bo Liang;Abraam M. Yakoub - 通讯作者:
Abraam M. Yakoub
Abraam M. Yakoub的其他文献
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{{ truncateString('Abraam M. Yakoub', 18)}}的其他基金
Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases
自噬:一种用于神经退行性疾病的自噬功能化基因治疗工具
- 批准号:
10334114 - 财政年份:2022
- 资助金额:
$ 45.71万 - 项目类别:
Autophagon: an Autophagy-Functionalizing Gene Therapy Tool for Neurodegenerative Diseases
自噬:一种用于神经退行性疾病的自噬功能化基因治疗工具
- 批准号:
10589751 - 财政年份:2022
- 资助金额:
$ 45.71万 - 项目类别:
Establishing Cellular Models of SARS-CoV2 Infection for COVID-19 Studies
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- 批准号:
9924569 - 财政年份:2020
- 资助金额:
$ 45.71万 - 项目类别:
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