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

批准号：
10811050
负责人：
Cedric G Geoffroy
金额：
$ 41.11万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
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：
2023-09-18 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811050
关键词：
2 year old Adult Age Age Months Age Years Aging American Animals Biological Assay Biological Availability Brain Cell Survival Cells Characteristics Chest Clinical Contusions Corticospinal Tracts Data Development Drug Approval Processes Drug Screening Elderly Embryo FDA approved Failure Female Future Gait Goals Hour Human Image Inflammation Injury Libraries Locomotion Locomotor Recovery Mammals Metabolism Modeling Molecular Mus Nervous System Physiology Nervous System Trauma Neurites Neurodegenerative Disorders Neurons Paralysed Patients Pattern Performance Pharmaceutical Preparations Phase Phenotype Population Process Publishing Recovery Recovery of Function Regenerative capacity Reporting Robotics Rodent Model Rotarod Performance Test Sheep Spinal Cord Spinal cord injury Spinal cord injury patients Systems Analysis Technology Testing Therapeutic Time Work axon growth brain tissue care costs clinical translation clinically relevant cost cost effective demographics efficacy evaluation improved in vivo intraperitoneal male mouse model nervous system disorder neurite growth neuron loss neuronal survival neuroprotection neurotoxicity novel novel therapeutics personalized medicine postnatal pre-clinical preclinical efficacy premature research clinical testing screening sex success therapeutic candidate

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 130 万美国人因脊髓损伤 (SCI) 而瘫痪，给我们的经济造成了数十亿美元的损失每年。迄今为止，尚无 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并增强成年皮质神经元的再生能力，以在不同部位形成连接通过皮质脊髓束调节脊髓水平是促进 SCI 后恢复的关键。理想情况下，候选治疗应针对皮质神经细胞（CNC）进行筛查。然而，目前的筛选技术仅利用胚胎或产后早期神经细胞，不代表 SCI 患者人口统计，其中大多数是 20多岁或60多岁的小鼠，分别相当于6个月大和18个月大的小鼠。使用具有以下特征的神经细胞与临床环境中的靶细胞不同，如果不考虑年龄，会导致转化成功率较低。此外，当前的筛查不区分性别，而神经系统疾病和创伤可能与性别相关（78% SCI 患者为男性）。与年龄和性别相适应的药物筛查以前并不可信，导致错误的结果积极和消极可以解释许多药物在临床阶段的失败。开发截屏年龄和性别作为变量会增加转化成功的机会。我们的长期目标是开发新的治疗方案，促进 SCI 患者的康复。主要目标该提案的目的是寻找能够改善 SCI 临床前小鼠模型恢复的新化合物。 3步开发了使用成年羊和小鼠 CNC 的筛选平台，其中包括物种、年龄和性别作为变量。这是第一个以高通量方式使用 CNC 的屏幕，也是第一个能够使用大型哺乳动物脑组织的屏幕。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中提供大量 CNC 纯度高，具有成本效益的屏幕； 2) 发现对成年人有益的化合物，但被其他筛选过早地忽视了；和 3) 确定筛选化合物小鼠和绵羊的种间功效），增加了被筛选的化合物的可能性对人类有效。在 2 岁成年绵羊 CNC 中进行了超过 1,200 种独特化合物的针对性筛选（鉴定神经系统疾病临床测试中的药物）以及 6 个月和 18 个月大的雄性/雌性小鼠 CNC。 4 在 SCI 小鼠模型中测试了阳性命中，3 促进了功能恢复。这验证了该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，在来自不同物种、年龄和性别组的成人 CNC 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传统筛选，2) 识别具有与人口统计学无关的功效的药物。该提案将筛选 L1000 批准的药物库（>2,800 种药物）寻找 4 个线索（目标 1）并确定它们在促进功能性方面的功效在临床相关的 SCI 小鼠模型中恢复（目标 2）。研究结束时，至少有一种新药可以增强恢复将被揭开。未来的研究将包括了解药物的细胞和分子机制收集支持 IND 的数据，用于未来在不断老龄化的 SCI 人群中进行临床测试。