Novel therapy for Fragile X syndrome
脆性 X 综合征的新疗法
基本信息
- 批准号:9465071
- 负责人:
- 金额:$ 39.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2019-07-31
- 项目状态:已结题
- 来源:
- 关键词:Alpha CellAnimal ModelAutistic DisorderBehavioralBiochemicalBiological AssayBrainCYP2D6 geneCYP3A4 geneCellsCerebrumCharacteristicsChemistryClinical TrialsComputer SimulationDendritic SpinesDevelopmentDiseaseDisease modelDoseDrug InteractionsDrug KineticsEnzymesExhibitsFMR1Fragile X SyndromeGeneticGoalsHigh Pressure Liquid ChromatographyHomeostasisHumanImpaired cognitionImpairmentIn VitroInheritedIntellectual functioning disabilityInterventionKineticsLaboratoriesLeadLearningLigandsLiver MicrosomesLong-Term DepressionMemoryModelingMolecular AbnormalityMorphologyMusNeuronsOralOral AdministrationOrganoidsOutcomePathway AnalysisPatientsPermeabilityPharmaceutical PreparationsPharmacologyPhasePhenotypePhosphorylationPhosphotransferasesPlayPreclinical Drug EvaluationProblem behaviorPropertyProtein BiosynthesisProteinsProtocols documentationPyrimidineResearchRibosomal Protein S6 KinaseRibosomesRiskRoleSeriesSignal TransductionSmall Business Innovation Research GrantSocial InteractionSolubilityStructural ProteinSynapsesTechnologyTestingTherapeuticTranslationsVertebral columnWeight GainWorkautism spectrum disorderbasedesigndrug candidatedrug developmentefficacy evaluationefficacy testingepigenimprovedin vivoinduced pluripotent stem cellinhibitor/antagonistinnovationmeetingsmouse modelmulti-electrode arraysnovelnovel therapeuticsobject recognitionpharmacophorepre-clinicalpreventprogramsreceptorscaffoldsmall moleculesmall molecule inhibitorsynaptogenesistreatment strategy
项目摘要
PROJECT SUMMARY
Fragile X syndrome (FXS) is the most common inheritable form of cognitive impairment and the leading known
genetic cause of autism. FXS is caused by the loss of expression of the fragile X mental retardation protein
(FMRP). A major challenge for FXS research is to develop treatment strategies that improve the intellectual
capabilities of patients. Dysregulated protein synthesis is widely accepted as a core molecular abnormality
associated with FXS. Because neuronal protein synthesis is critical for learning and memory, altered synaptic
translation is considered a major contributor to the intellectual deficits seen in FXS. Currently available
pharmacological intervention strategies for FXS primarily treat behavioral problems and have focused largely
on targets upstream of translational control to normalize FXS-related phenotypes. We have identified a specific
target that is a common downstream effector of both mTORC1 and ERK signaling and plays a direct role in
regulating translation. Genetic deletion of the target in an animal model of FXS corrected exaggerated protein
synthesis and other biochemical, neuroanatomical and behavioral abnormalities associated with FXS. These
results suggest a strategy for developing a disease modifying therapeutic for FXS. By using a rational design
approach that combines structural protein information and optimal ADME properties, we have discovered a
novel series of potent inhibitors. Epigen has developed specific and drug-like small molecule inhibitors to this
target, as exemplified by lead compound EPGN1370. We have teamed up with Dr. Alysson Muotri's
laboratories at UCSD to propose a novel discovery paradigm for effective drug candidate compounds for FXS
by using newly developed cerebral organoids, or “mini-brains” to model the disease in 3D in the laboratory.
The goal of this phase 1 SBIR work is to conduct focused lead optimization of our newly discovered series of
novel inhibitors as agents to treat FXS. In this work, new compounds will be identified utilizing our assay
cascade combining in vitro receptor pharmacology, ADME assays and mouse pharmacokinetics to select 1-3
advanced lead molecules, which will be evaluated in a human FXS “mini-brain”. The best advanced lead
identified will be evaluated in a mouse model of FXS for biochemical and neuroanatomical outcomes. This
work will set the stage for detailed in vivo pharmacology assessment and IND-enabling studies in the phase 2
SBIR. Our study will open up a new avenue of target-specific drug development for Autism Spectrum Disorders
such as FXS.
项目摘要
脆性X综合征(FXS)是认知障碍的最常见的遗传形式,也是已知的最主要的认知障碍。
自闭症的遗传原因FXS是由脆性X智力低下蛋白表达缺失引起的
(FMRP)。FXS研究的一个主要挑战是开发治疗策略,
患者的能力。蛋白质合成失调被广泛认为是核心分子异常
与FXS有关。由于神经元蛋白质合成对学习和记忆至关重要,
翻译被认为是导致FXS智力缺陷的主要因素。当前可用
FXS的药物干预策略主要治疗行为问题,
在翻译控制的上游靶点上使FXS相关表型正常化。我们发现了一种
靶点是mTORC 1和ERK信号传导的共同下游效应物,并在
规范翻译。FXS校正的夸大蛋白动物模型中靶基因缺失
合成和其他与FXS相关的生化、神经解剖学和行为异常。这些
结果提示了开发FXS的疾病改善治疗剂的策略。通过合理的设计
结合结构蛋白质信息和最佳ADME特性的方法,我们发现了一种
一系列新的强效抑制剂。Epigen为此开发了特异性和药物样小分子抑制剂
靶向,如先导化合物EPGN 1370所例示。我们与Alysson Muotri博士合作,
UCSD的实验室提出了一种新的发现范式,用于FXS的有效药物候选化合物
通过使用新开发的大脑类器官或“迷你大脑”在实验室中以3D方式模拟疾病。
第一阶段SBIR工作的目标是对我们新发现的一系列
作为治疗FXS的药剂的新抑制剂。在这项工作中,新的化合物将被确定利用我们的测定
级联组合体外受体药理学、ADME测定和小鼠药代动力学以选择1-3
先进的铅分子,将在人类FXS“迷你大脑”中进行评估。最先进的领先
将在FXS的小鼠模型中评估鉴定的生物化学和神经解剖学结果。这
这项工作将为2期详细的体内药理学评估和IND使能研究奠定基础
SBIR。我们的研究将为自闭症谱系障碍的靶向药物开发开辟一条新的途径
例如FXS。
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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Alysson R. Muotri其他文献
Generation of ‘semi-guided’ cortical organoids with complex neural oscillations
具有复杂神经振荡的“半引导”皮质类器官的生成
- DOI:
10.1038/s41596-024-00994-0 - 发表时间:
2024-05-03 - 期刊:
- 影响因子:16.000
- 作者:
Michael Q. Fitzgerald;Tiffany Chu;Francesca Puppo;Rebeca Blanch;Miguel Chillón;Shankar Subramaniam;Alysson R. Muotri - 通讯作者:
Alysson R. Muotri
ヒトiPS細胞からブレインオルガノイドを作製する
利用人类 iPS 细胞创建大脑类器官
- DOI:
- 发表时间:
2017 - 期刊:
- 影响因子:0
- 作者:
中嶋 秀行;Cleber A. Trujillo;石津 正崇;潘 淼;Alysson R. Muotri;中島 欽一 - 通讯作者:
中島 欽一
The impact of antidepressants on human neurodevelopment: Brain organoids as experimental tools
抗抑郁药对人类神经发育的影响:脑类器官作为实验工具
- DOI:
10.1016/j.semcdb.2022.09.007 - 发表时间:
2023-07-30 - 期刊:
- 影响因子:6.000
- 作者:
Luciana Simões Rafagnin Marinho;Gabrielly Maria Denadai Chiarantin;Juliane Midori Ikebara;Débora Sterzeck Cardoso;Théo Henrique de Lima-Vasconcellos;Guilherme Shigueto Vilar Higa;Mariana Sacrini Ayres Ferraz;Roberto De Pasquale;Silvia Honda Takada;Fabio Papes;Alysson R. Muotri;Alexandre Hiroaki Kihara - 通讯作者:
Alexandre Hiroaki Kihara
Graphene-polymer nanofibers enable optically induced electrical responses in stem cell-derived electrically excitable cells and brain organoids
石墨烯 - 聚合物纳米纤维使干细胞衍生的可兴奋电细胞和脑类器官能够产生光诱导的电响应
- DOI:
10.1016/j.biomaterials.2025.123430 - 发表时间:
2025-12-01 - 期刊:
- 影响因子:12.900
- 作者:
Erin LaMontagne;Alex Savchenko;Gisselle Gonzalez;Ritwik Vatsyayan;Blanca Martin-Burgos;Francesca Puppo;Diogo Biagi;Fabio Papes;Shadi A. Dayeh;Alysson R. Muotri;Adam J. Engler - 通讯作者:
Adam J. Engler
Peering into the mind: unraveling schizophrenia’s secrets using models
窥视心灵:利用模型揭示精神分裂症的秘密
- DOI:
10.1038/s41380-024-02728-w - 发表时间:
2024-09-08 - 期刊:
- 影响因子:10.100
- 作者:
João V. Nani;Alysson R. Muotri;Mirian A. F. Hayashi - 通讯作者:
Mirian A. F. Hayashi
Alysson R. Muotri的其他文献
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{{ truncateString('Alysson R. Muotri', 18)}}的其他基金
Impact of prenatal inflammation on developing human brain
产前炎症对人类大脑发育的影响
- 批准号:
10705556 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
A new brain organoid model for NeuroHIV and the impact of opioids
NeuroHIV 的新脑类器官模型以及阿片类药物的影响
- 批准号:
10693976 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
Establishment of a causal link between AD and L1 retrotransposons
AD 和 L1 反转录转座子之间因果关系的建立
- 批准号:
10519029 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
A new brain organoid model for NeuroHIV and the impact of opioids
NeuroHIV 的新脑类器官模型以及阿片类药物的影响
- 批准号:
10529106 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
Establishment of a causal link between AD and L1 retrotransposons
AD 和 L1 反转录转座子之间因果关系的建立
- 批准号:
10704226 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
Impact of prenatal inflammation on developing human brain
产前炎症对人类大脑发育的影响
- 批准号:
10387980 - 财政年份:2022
- 资助金额:
$ 39.99万 - 项目类别:
The impact of hiPSC-derived microglia in human brain development in health and disease
hiPSC 衍生的小胶质细胞对健康和疾病中人脑发育的影响
- 批准号:
10279492 - 财政年份:2021
- 资助金额:
$ 39.99万 - 项目类别:
Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model
使用人体模型研究皮特霍普金斯综合症的病理生理学
- 批准号:
10553718 - 财政年份:2021
- 资助金额:
$ 39.99万 - 项目类别:
Investigation of Pitt-Hopkins Syndrome pathophysiology using a human model
使用人体模型研究皮特霍普金斯综合症的病理生理学
- 批准号:
10208365 - 财政年份:2021
- 资助金额:
$ 39.99万 - 项目类别:
The Impact of hiPSC-Derived Microglia in Human Brain Development in Health and Disease
hiPSC 衍生的小胶质细胞对健康和疾病中人脑发育的影响
- 批准号:
10458040 - 财政年份:2021
- 资助金额:
$ 39.99万 - 项目类别:
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