A novel adult neurons screening technology to repurpose FDA-approved drugs for spinal cord injury

一种新型成人神经元筛选技术,可重新利用 FDA 批准的治疗脊髓损伤的药物

基本信息

项目摘要

About 1.3 million Americans suffer from paralysis due to spinal cord injury (SCI) costing our economy billions of dollars each year. To date, no FDA-approved therapeutic options exist for SCI, demonstrating the need for new therapeutic options. Reducing neuronal cell death and enhancing regenerative capacities of adult cortical neurons to form connections at different levels of the spinal cord via the corticospinal tract are keys to increasing recovery after SCI. Ideally, candidate therapeutic screenings should be conducted on cortical neural cells (CNCs). However, current screening technologies only utilize embryonic or early post-natal neural cells, which do not represent the SCI patient demographic, majority of whom are either in their 20s or 60s, equivalent to mice of 6 and 18 months of age, respectively. Using neural cells with characteristics that differ from the targeted cells in clinical settings, without taking age into consideration, results in low translational success. Additionally, current screens do not differentiate for sex, while neurological diseases and trauma can be sex dependent (78% of SCI patients are male). Age- and sex-appropriate drug screens have previously not been plausible resulting in false positives and negatives which can explain the failure of many drugs during the clinical phases. Developing a screen taking age and sex as variables would increase the chance of translational success. Our long-term goal is to develop novel therapeutic options that enhance recovery for patients with SCI. The main objective during this proposal is to find new compounds that improve recovery in a pre-clinical mouse model of SCI. A 3-step screening platform using adult sheep and mice CNCs that includes species, age and sex as variables was developed. This is the first screen using CNCs in a high-throughput fashion and the first capable of using brain tissue from large mammals. This technology 1) reduces processing time and animal use while providing a high number of CNCs at increased neuron purity for a cost-effective screen; 2) finds compounds beneficial to adults prematurely dismissed by other screens; and 3) determines the interspecies efficacy of the screened compounds mouse and sheep), increasing the likelihood of being effective in humans. A targeted screen of >1,200 unique compounds was conducted in 2-years-old adult sheep CNCs (identifying drugs in clinical testing for neurological disorders) and in 6 and 18-month-old male/female mice CNCs. 4 positive hits were tested in a mouse model of SCI, 3 promoted functional recovery. This validates the use of this technology to find compounds with pre-clinical efficacy and potential clinical translation. The overarching hypothesis is that screening of approved drugs in adult CNCs from various species, age and sex groups will increase the pre-clinical success rate by 1) uncovering beneficial drugs previously dismissed or untested in conventional screens, and 2) identifying drugs with demographics-independent efficacies. This proposal will screen the L1000 Approved Drug Library (>2,800 drugs) to find 4 leads (Aim 1) and determine their efficacy in promoting functional recovery in a clinically relevant mouse model of SCI (Aim 2). At the end of the studies, at least one novel drug enhancing recovery will be uncovered. Future studies will include understanding the cellular and molecular mechanisms of the drug and gathering IND-enabling data for future clinical testing in the ever-aging SCI population.
大约有130万美国人因脊髓损伤(SCI)而瘫痪,造成数十亿美元的经济损失。 每年.到目前为止,还没有FDA批准的SCI治疗方案,这表明需要新的治疗方案。 减少神经元细胞死亡和增强成年皮层神经元的再生能力,以在不同时间形成连接。 通过皮质脊髓束的脊髓水平是增加SCI后恢复的关键。理想情况下,候选治疗 应该对皮层神经细胞(CNCs)进行筛查。然而,目前的筛选技术仅利用 胚胎或出生后早期的神经细胞,不代表SCI患者的人口统计学,其中大多数是 20多岁或60多岁,分别相当于6个月和18个月大的小鼠。利用神经细胞的特性, 在临床环境中,如果不考虑年龄,与靶细胞不同,则导致低翻译成功率。 此外,目前的筛查没有区分性别,而神经系统疾病和创伤可能依赖于性别(78%)。 SCI患者为男性)。与年龄和性别相适应的药物筛选以前并不合理,导致错误的 阳性和阴性,这可以解释许多药物在临床阶段的失败。开发屏幕拍摄 年龄和性别作为变量将增加翻译成功的机会。 我们的长期目标是开发新的治疗方案,以促进SCI患者的康复。主要目标 该提案的目的是寻找新的化合物来改善SCI临床前小鼠模型的恢复。3步 筛选平台使用成年绵羊和小鼠的CNCs,包括物种,年龄和性别作为变量。这是 第一个筛选使用CNCs以高通量的方式,第一个能够使用来自大型哺乳动物的脑组织。 该技术1)减少了处理时间和动物使用,同时在增加的神经元数量下提供了大量的CNC, 2)发现对被其他筛选过早排除的成年人有益的化合物;以及3) 确定筛选的化合物的种间功效(小鼠和绵羊),增加了被 对人类有效。在2岁成年绵羊CNCs中进行了> 1,200种独特化合物的靶向筛选 (在神经系统疾病的临床试验中鉴定药物)和6和18个月大的雄性/雌性小鼠CNC。4 在SCI的小鼠模型中测试阳性命中,3促进功能恢复。这验证了这项技术的使用 寻找具有临床前疗效和潜在临床转化的化合物。 总体假设是,在不同物种、年龄和性别组的成人CNCs中筛选批准的药物, 将通过以下方式提高临床前成功率:1)发现以前被驳回或未经测试的有益药物, 常规筛选,以及2)鉴定具有人口统计学独立功效的药物。该提案将筛选 L1000批准的药物库(> 2,800种药物),以找到4种先导药物(目标1),并确定其在促进功能性 在SCI的临床相关小鼠模型中的恢复(目的2)。在研究结束时,至少有一种新的药物增强了 复苏将被揭开。未来的研究将包括了解药物的细胞和分子机制 并收集IND使能数据,用于未来在不断老龄化的SCI人群中进行临床试验。

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 }}

Cedric G Geoffroy其他文献

Cedric G Geoffroy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('Cedric G Geoffroy', 18)}}的其他基金

Understanding the age-dependent mitochondrial function in astrocytes after spinal cord injury via bi-directional manipulation of activity
通过双向操纵活性了解脊髓损伤后星形胶质细胞的年龄依赖性线粒体功能
  • 批准号:
    10503483
  • 财政年份:
    2022
  • 资助金额:
    $ 41.11万
  • 项目类别:
Understanding the age-dependent mitochondrial function in astrocytes after spinal cord injury via bi-directional manipulation of activity
通过双向操纵活性了解脊髓损伤后星形胶质细胞的年龄依赖性线粒体功能
  • 批准号:
    10662520
  • 财政年份:
    2022
  • 资助金额:
    $ 41.11万
  • 项目类别:

相似海外基金

Developing a Young Adult-Mediated Intervention to Increase Colorectal Cancer Screening among Rural Screening Age-Eligible Adults
制定年轻人介导的干预措施,以增加农村符合筛查年龄的成年人的结直肠癌筛查
  • 批准号:
    10653464
  • 财政年份:
    2023
  • 资助金额:
    $ 41.11万
  • 项目类别:
Doctoral Dissertation Research: Estimating adult age-at-death from the pelvis
博士论文研究:从骨盆估算成人死亡年龄
  • 批准号:
    2316108
  • 财政年份:
    2023
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Standard Grant
Determining age dependent factors driving COVID-19 disease severity using experimental human paediatric and adult models of SARS-CoV-2 infection
使用 SARS-CoV-2 感染的实验性人类儿童和成人模型确定导致 COVID-19 疾病严重程度的年龄依赖因素
  • 批准号:
    BB/V006738/1
  • 财政年份:
    2020
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Research Grant
Transplantation of Adult, Tissue-Specific RPE Stem Cells for Non-exudative Age-related macular degeneration (AMD)
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 (AMD)
  • 批准号:
    10294664
  • 财政年份:
    2020
  • 资助金额:
    $ 41.11万
  • 项目类别:
Sex differences in the effect of age on episodic memory-related brain function across the adult lifespan
年龄对成人一生中情景记忆相关脑功能影响的性别差异
  • 批准号:
    422882
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Operating Grants
Modelling Age- and Sex-related Changes in Gait Coordination Strategies in a Healthy Adult Population Using Principal Component Analysis
使用主成分分析对健康成年人群步态协调策略中与年龄和性别相关的变化进行建模
  • 批准号:
    430871
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Studentship Programs
Transplantation of Adult, Tissue-Specific RPE Stem Cells as Therapy for Non-exudative Age-Related Macular Degeneration AMD
成人组织特异性 RPE 干细胞移植治疗非渗出性年龄相关性黄斑变性 AMD
  • 批准号:
    9811094
  • 财政年份:
    2019
  • 资助金额:
    $ 41.11万
  • 项目类别:
Study of pathogenic mechanism of age-dependent chromosome translocation in adult acute lymphoblastic leukemia
成人急性淋巴细胞白血病年龄依赖性染色体易位发病机制研究
  • 批准号:
    18K16103
  • 财政年份:
    2018
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Doctoral Dissertation Research: Literacy Effects on Language Acquisition and Sentence Processing in Adult L1 and School-Age Heritage Speakers of Spanish
博士论文研究:识字对西班牙语成人母语和学龄传统使用者语言习得和句子处理的影响
  • 批准号:
    1823881
  • 财政年份:
    2018
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Standard Grant
Adult Age-differences in Auditory Selective Attention: The Interplay of Norepinephrine and Rhythmic Neural Activity
成人听觉选择性注意的年龄差异:去甲肾上腺素与节律神经活动的相互作用
  • 批准号:
    369385245
  • 财政年份:
    2017
  • 资助金额:
    $ 41.11万
  • 项目类别:
    Research Grants
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了