TDP-43 Proteinopathies

▎药明康德内容团队编辑  作为最常见的神经退行性疾病，阿尔茨海默病会严重损伤记忆、思考能力，最终可能导致死亡。阿尔茨海默病的一个典型症状是β淀粉样蛋白斑块，β淀粉样蛋白在大脑中堆积，导致的神经缠结与大脑萎缩以及认知能力下降密切相关。2023年，FDA完全批准的近20年来首款阿尔茨海默病新药lecanemab，正是通过抗体与β淀粉样蛋白特异性结合而起到治疗效果，成功改变阿尔茨海默病进程。现在，来自圣路易斯华盛顿大学的研究团队在一篇《科学-转化医学》论文中，展示了一种清除毒性蛋白斑块的新策略：通过抗体恢复神经系统免疫细胞的蛋白清理能力，直接动员自身的小胶质细胞来减少淀粉样蛋白沉积。在小鼠实验中，这款全新的免疫疗法能够成功减少毒性斑块，并减轻阿尔茨海默病样小鼠的行为异常，因此成为一款极具前景的潜在疗法。小胶质细胞是中枢神经系统中最重要的一类免疫细胞，正常情况下，它们会围绕着淀粉样蛋白斑块形成一道屏障，控制有害蛋白的扩散，并且还可以吞噬、破坏这些蛋白斑块。但在阿尔茨海默病中，小胶质细胞清理斑块的能力明显减弱了，而这一差异可能与ApoE蛋白有关。作为淀粉样蛋白斑块的组成部分，ApoE蛋白能够与斑块周围小胶质细胞上的白细胞免疫球蛋白样受体LILRB4结合，抑制小胶质细胞的活性。研究团队在检查阿尔茨海默病患者的脑组织切片时发现，患者的小胶质细胞表面有大量LILRB4受体；使用表达人类LILRB4受体的转基因小鼠模型，研究团队进一步证实了这一发现，并且证实LILRB4抑制了小胶质细胞清除β淀粉样蛋白斑块的能力。▲在阿尔茨海默病大脑中，β淀粉样蛋白斑块周围的ApoE蛋白（白色）与LILRB4受体（红色）结合（图片来源：参考资料[1]）上述发现也为治疗指出了潜在的路线。研究团队设计了针对人类LILRB4的单抗，并且对大脑中有β淀粉样蛋白斑块的小鼠模型进行了治疗，发现该抗体阻止了ApoE与LILRB4的结合，增强了小胶质细胞的活性。这些被激活的小胶质细胞，也有效减少了小鼠大脑中的斑块。▲与对照组相比，抗体治疗有效减少了阿尔茨海默病小鼠大脑中的淀粉样蛋白斑块（蓝色）（图片来源：参考资料[1]）全新抗体的使用也在行为测试中造成行为变化，减轻了小鼠的冒险行为。阿尔茨海默病患者往往会缺乏对过去经历的记忆，因此可能会做出冒险行为，例如更容易受骗。而用于清除蛋白斑块的抗体治疗，则显示出了改变行为的潜力。值得注意的是，直接靶向淀粉样斑块的药物可能会引起潜在的严重副作用。在阿尔茨海默病患者中，β淀粉样蛋白堆积在大脑动脉壁以及脑组织的其他部位。如果清除的是脑血管中的斑块，则可能会引起肿胀和出血，这种副作用被称为淀粉样蛋白相关影像异常（ARIA）。这项研究中使用的小鼠在血管上缺乏淀粉样斑块，因此研究人员尚无法评估这种副作用是否存在。目前，他们正在一种脑动脉上长有斑块的小鼠模型中检验这种风险。图片来源：123RF“Lecanemab作为首个能够改变疾病进程的治疗性抗体，证实了β淀粉样蛋白在阿尔茨海默病进展中的重要性，”论文作者David Holtzman教授说，“它为开发其他免疫疗法提供了新的机遇，这些疗法使用不同的方法来清除大脑中的有害蛋白。”研究团队指出，由于有毒的蛋白斑块不仅与阿尔茨海默病有关，还是帕金森病、肌萎缩侧索硬化症和亨廷顿病等多种神经退行性疾病的特征，因此这种免疫疗法可能会对更广泛的神经退行性疾病治疗产生深远影响。目前，研究团队也在探索其他潜在的免疫疗法，以清除可能促进其他疾病的有害蛋白。参考资料：[1] Jinchao Hou et al, Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adj9052[2] Immunotherapy for Alzheimer’s disease shows promise in mouse study. Retrieved Apr. 4, 2024 from https://www.eurekalert.org/news-releases/1039990本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。更多推荐点个“在看”再走吧~

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CLOSED 6 BILLION DOLLAR SERIES B DEALSAN FRANCISCO, April 05, 2024 (GLOBE NEWSWIRE) -- Silicon Valley-based Neurotechnology Powerhouse, announced that it launched its non-invasive iBrain™ Personal Brain Monitor, in 4 US states on Friday and sold 1.4% of its stock for more than $85 million, valuing the company at over $6 Billion in the highest Series B financing in History by a margin of $4.5 Billion, at over 12 times Facebook’s Series B valuation. The invitation-only financing itself, with 27 Strategic Investors, including a major Hospital, a leading University, an American Super Angel, 3 elite VCs, 5 pioneering Clinics and 7 top Law Firms, who favored backing scalable non-invasive brain technology over limited and invasive ones, only took 24 minutes to close. “Who needs implants when you have the real deal?” said Dr. Philip Low, PhD, NeuroVigil’s Chairman, Chief Executive and Technology Officer, Founder and Supermajority Owner. In the first phase of the launch, iBrain, positioned as an investigational device, will hunt for biomarkers of apnea, aneurysms and drug side effects in asymptomatic individuals, as it has in partnership with Roche and Novartis, NeuroVigil’s first paying clients since well over a decade. The investigators will initially not be allowed to modify anyone’s therapy based on iBrain data. That can only happen following FDA-approved tests. In the second phase, NeuroVigil will release the smaller iBrain 3, and will look for signs of Brain Cancer and Parkinson’s, as well as empower individuals who cannot communicate, without drilling a hole in anyone’s head. The project was initiated at the request of late NeuroVigil advisor Stephen Hawking, in case he became locked-in, and its patent – the company favors patents over publicity stunts – is one of NeuroVigil’s 48 granted patents (the company has another 25 immediately pending applications) was fast-tracked by the USPTO. A joint abstract by Dr. Low and Dr. Hawking featuring Dr. Hawking’s brain patterns analyzed by NeuroVigil’s technology was released as early as 2012. The technology was also successfully demonstrated on ALS sufferer Augie Nieto in 2013 who spelled “COMMUNICATE” with his mind. In parallel, NeuroVigil, which is organized very much like an IP holding company but with a small crew of phenomenal contractors assisting clients, is exploring creating a joint venture with an American, a German and a Japanese car manufacturing conglomerate, to monitor drivers and, in part, to apply Dynamic Spectral Scoring (DSS) and other techniques to revolutionize the management of electric batteries for cars and trucks. An initial meeting with the German conglomerate took place in Stockholm in February. DSS was initially developed by Dr. Low when he was a graduate student at the Salk Institute on the personal recommendation of Francis Crick, late Nobel Laureate of DNA fame (who had seen Dr. Low’s work at Harvard Medical School when he was a teenager), and was summarized in his one-page PhD thesis. This technology acts like a super-sensitive radar for data by helping identify statistically significant shifts in data, no matter how imperceptible to humans, that can serve to detect in which state a system is and to forecast in which other state the system will transition to, in an unsupervised way, without using an embedded statistical model or training an AI to replicate human performance (and human biases). The technique was applied to a number of systems, and even showed that birds, without a neocortex, had mammalian-like brain patterns, which led to Dr. Low writing the Cambridge Declaration on Consciousness, the first formal document recognizing consciousness as not restricted to the human brain. “This technology is having tremendous impact” said the late Roger Guillemin, one of 4 Nobel Laureates who helped Dr. Low with NeuroVigil when he was a graduate student, before being full-time at NeuroVigil and Adjunct Professor at the Stanford School of Medicine and Research Affiliate at MIT. “Our mission is to create a universe where billions of people will be able to non-invasively access, communicate and leverage their brain state in real time,” said Dr. Low. Unlike laborious invasive BCIs which suffer usability issues due to challenges such as the body’s adaptation to the new implant and high cost associated with the scans, iBrain, dubbed as the “iPhone of Neuroscience,” is completely non-invasive, and does not even rely on any animal testing. In the past two years, NeuroVigil has recruited talent from Amgen, Roche, Novartis and MIT in preparation for the launch. Dr. Low, who has opted to decline stock incentives for himself since 2009 – he initially turned down VCs and government funding and slept in his San Diego office and grew the company organically with less than $5 million in investment over 17 years and holds between 80 and 90% of the stock - and a salary since 2017, has favored donating performance-based stock options to his team, including contractors and interns. He has furthermore created a Manhattan Project for the Brain™, an exclusive alliance of prominent investors and lawyers, trailblazing accelerators and medical personnel, to assist with the launch, and with subsidiaries and partners. The company has put aside an initial tranche of about $40 million in clinical support services to help other companies in the non-invasive biotech space test their technologies. “NeuroVigil’s bold plan of attack is several quantum leaps above anything else that has ever been envisioned, including by non-neuroscientists. This multidimensional technology has the potential to create a compendium of new industries and to take over the world by storm,” said Dr. Ashraf Elsayegh, MD, FCCP, FAASM, former head of the Divisions of Pulmonary / Critical Care / Intensive Care and Pulmonary Director of the neuromuscular clinic at Cedars-Sinai Medical Center, one of the most prestigious hospitals in the world, and Associate Clinical Professor at UCLA School of Medicine. His comments on NeuroVigil are echoed by international venture capitalist and futurist Sven Gabor Janszky, Chairman of 2b AHEAD ThinkTank and 2b AHEAD Ventures GmbH: "Deep Science, excellently applied into different fields. This is the highest ranked company in value and reputation I ever saw at this stage." Indeed, Dr. Low was recognized by MIT Technology Review as one of the Top Young Innovators, an honor shared with the founders of Google and Facebook, and NeuroVigil’s previous valuations were already over twice the Seed and Series A valuations of these companies combined. NeuroVigil was also named as one of the Top 10 Most Innovative Companies in Health Care and The New York Times identified iBrain as “an innovation that will change your tomorrow.” Contact:Ignacio Carullopress@neurovigil.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/c7202935-f121-4923-aa93-0daa2cecfdf3