Administrative supplement for Novel therapy for Fragile X syndrome

脆性 X 综合征新疗法的行政补充

基本信息

  • 批准号:
    10426007
  • 负责人:
  • 金额:
    $ 5万
  • 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 2022-03-31
  • 项目状态:
    已结题

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. Lead optimization efforts in the phase 1 STTR portion of the work identified EPGN2036 as a candidate for pharmacological evaluation. This compound dose-dependently corrected behavioral deficits in FMR1 KO2 mice after oral administration. Moreover, EPGN2036 demonstrated target engagement in hippocampal lysates of FMR1 KO mice treated with the compound. In collaboration with Dr. Alysson Muotri at UCSD, we have started development of brain organoids derived from FXS patients to model the disease in 3D in the laboratory. Preliminary safety studies in rats indicate that EPGN2036 has sufficient safety margin to warrant further investigation. The goal of this phase 2 SBIR work is to characterize the preclinical efficacy of EPGN2036 using a translatable biomarker of drug efficacy, evaluate drug-drug interaction potential of leads, conduct focused back-up / follow-up discovery and assess safety of select leads to determine development potential. Recent work demonstrated that EEG measures in FMR1 KO mice are in excellent agreement with EEG signals of FXS patients and that EEG could be used as a biomarker predictive of early disease modulation. As such, we will evaluate the effect of EPGN2036 on both mouse FMR1 KO mouse EEG and FXS brain organoids. At the end of the grant period, we expect to be in a position to select a development candidate for initiation of IND-enabling studies and progression to phase 1 clinical trials in humans for assessment of safety and tolerability of EPGN2036 in normal healthy volunteers.
项目总结

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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

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

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 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:
    $ 5万
  • 项目类别:

相似海外基金

Proton-secreting epithelial cells as key modulators of epididymal mucosal immunity - Administrative Supplement
质子分泌上皮细胞作为附睾粘膜免疫的关键调节剂 - 行政补充
  • 批准号:
    10833895
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
A Longitudinal Qualitative Study of Fentanyl-Stimulant Polysubstance Use Among People Experiencing Homelessness (Administrative supplement)
无家可归者使用芬太尼兴奋剂多物质的纵向定性研究(行政补充)
  • 批准号:
    10841820
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
StrokeNet Administrative Supplement for the Funding Extension
StrokeNet 资助延期行政补充文件
  • 批准号:
    10850135
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
2023 NINDS Landis Mentorship Award - Administrative Supplement to NS121106 Control of Axon Initial Segment in Epilepsy
2023 年 NINDS 兰迪斯指导奖 - NS121106 癫痫轴突初始段控制的行政补充
  • 批准号:
    10896844
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Biomarkers of Disease in Alcoholic Hepatitis Administrative Supplement
酒精性肝炎行政补充剂中疾病的生物标志物
  • 批准号:
    10840220
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Administrative Supplement: Life-Space and Activity Digital Markers for Detection of Cognitive Decline in Community-Dwelling Older Adults: The RAMS Study
行政补充:用于检测社区老年人认知衰退的生活空间和活动数字标记:RAMS 研究
  • 批准号:
    10844667
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Administrative Supplement: Improving Inference of Genetic Architecture and Selection with African Genomes
行政补充:利用非洲基因组改进遗传结构的推断和选择
  • 批准号:
    10891050
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Power-Up Study Administrative Supplement to Promote Diversity
促进多元化的 Power-Up 研究行政补充
  • 批准号:
    10711717
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Administrative Supplement for Peer-Delivered and Technology-Assisted Integrated Illness Management and Recovery
同行交付和技术辅助的综合疾病管理和康复的行政补充
  • 批准号:
    10811292
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
Administrative Supplement: Genome Resources for Model Amphibians
行政补充:模型两栖动物基因组资源
  • 批准号:
    10806365
  • 财政年份:
    2023
  • 资助金额:
    $ 5万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了