微重力和太空环境与神经肌肉和认知能力的缺陷有关,假设是由于太空中加速老化和神经变性而发生的。虽然具体机制仍在调查中,航天相关的神经病理学是对宇航员和航天游客的重要健康风险,正在积极研究以制定相应的对策。然而,这种空间诱导的神经病理学为加速筛选用于治疗神经退行性疾病的治疗靶标和先导分子提供了机会。这里,我们展示了一个概念验证高通量目标筛选(在地球上),目标验证,使用我们的纳米低聚物平台缓解微重力诱导的神经病理学,在为期43天的SpaceXCRS-29国际空间站任务上。首先,比较3D健康和患病的前额叶皮层(PFC,用于认知)和运动神经元(MN,对于神经肌肉功能)类器官,我们使用与阿尔茨海默病(AD)相关的生物标志物评估空间诱导的病理学,额颞叶痴呆(FTD),和肌萎缩侧索硬化症(ALS)。健康和患病的PFC和MN类器官均显示出明显增强的空间神经变性,通过相关疾病生物标志物测量,与他们各自的地球控制相比。第二,我们测试了前两个铅分子,NI112靶向NF-κB和NI113靶向IL-6。我们观察到这些纳米低聚物显著减轻了AD,FTD,和ALS相关的生物标志物,如淀粉样β-42(Aβ42),磷酸化tau(pTau),Kallikrein(KLK-6),焦油DNA结合蛋白43(TDP-43),和其他人。此外,对这些脑类器官的43天纳米低聚物治疗似乎没有在目标类器官组织中引起任何可观察到的毒性或安全性问题,表明在生理相关剂量下,大脑中这些分子具有良好的耐受性。一起,这些结果表明,NI112和NI113分子的开发和翻译具有巨大的潜力,可以作为更安全的太空旅行的潜在神经保护对策,并证明了太空环境对快速,用于临床翻译的靶标和前导分子的高通量筛选。我们断言,在药物开发和筛选中使用微重力可能最终使地球上数百万患有衰弱神经退行性疾病的患者受益。
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microgravity and space environment has been linked to deficits in neuromuscular and cognitive capabilities, hypothesized to occur due to accelerated aging and neurodegeneration in space. While the specific mechanisms are still being investigated, spaceflight-associated neuropathology is an important health risk to astronauts and space tourists and is being actively investigated for the development of appropriate countermeasures. However, such space-induced neuropathology offers an opportunity for accelerated screening of therapeutic targets and lead molecules for treating neurodegenerative diseases. Here, we show a proof-of-concept high-throughput target screening (on Earth), target validation, and mitigation of
microgravity-induced neuropathology using our Nanoligomer platform, onboard the 43-day SpaceX CRS-29 mission to the International Space Station. First, comparing 3D healthy and diseased prefrontal cortex (PFC, for cognition) and motor neuron (MN, for neuromuscular function) organoids, we assessed space-induced pathology using biomarkers relevant to Alzheimer\'s disease (AD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). Both healthy and diseased PFC and MN organoids showed significantly enhanced neurodegeneration in space, as measured through relevant disease biomarkers, when compared to their respective Earth controls. Second, we tested the top two lead molecules, NI112 that targeted NF-κB and NI113 that targeted IL-6. We observed that these Nanoligomers significantly mitigate the AD, FTD, and ALS relevant biomarkers like amyloid beta-42 (Aβ42), phosphorylated tau (pTau), Kallikrein (KLK-6), Tar DNA-binding protein 43 (TDP-43), and others. Moreover, the 43-day Nanoligomer treatment of these brain organoids did not appear to cause any observable toxicity or safety issues in the target organoid tissue, suggesting good tolerability for these molecules in the brain at physiologically relevant doses. Together, these results show significant potential for both the development and translation of NI112 and NI113 molecules as potential neuroprotective countermeasures for safer space travel and demonstrate the usefulness of the space environment for rapid, high-throughput screening of targets and lead molecules for clinical translation. We assert that the use of
microgravity in drug development and screening may ultimately benefit millions of patients suffering from debilitating neurodegenerative diseases on Earth.