TAU

本期话题：肠脑轴，抑郁症，阿尔茨海默病，帕金森病，长寿老人，生殖，肠骨轴，肠肝轴，益普生，Infinant Health，Momo Kombucha，Aloha，健合集团 该篇日报由R·AI辅助创作生成，人工审核校对。 贾伟/刘铁民/郑晓皎Cell子刊：肠菌代谢物调节突触完整性，或可改善抑郁症 Cell Metabolism——[29] ① 上海交通大学贾伟、郑晓皎和复旦大学刘铁民与团队发表最新研究，揭示了肠菌产生的神经活性物质高香草酸（HVA）通过调节突触完整性来缓解抑郁症的机制，为抑郁症治疗提供了新思路；② 抑郁症患者和抑郁模型小鼠中，肠道菌群改变，长双歧杆菌（Bl）和肠罗斯氏菌（Ri）减少，伴随血液HVA水平降低；③ Ri能在肠道中促进Bl丰度，而Bl可利用酪氨酸等底物生成HVA；④ 在2种抑郁模型小鼠中，补充HVA、Bl或Ri均能显著改善抑郁症状；⑤ 肠源性HVA能跨越血脑屏障进入大脑，通过抑制微管相关蛋白1轻链3（LC3）和SQSTM1/p62蛋白的过度降解来防止突触自噬性死亡，保护海马体神经元突触前膜。 【原文信息】 Gut bacteria-driven homovanillic acid alleviates depression by modulating synaptic integrity 2024-04-05 , doi: 10.1016/j.cmet.2024.03.010 阿尔茨海默病的内毒素假说（综述） Molecular Neurodegeneration——[15.1] ① 提出并支持内毒素假说，认为脂多糖（LPS）可能通过促进淀粉样蛋白病理、Tau蛋白病理和小胶质细胞激活，从而参与阿尔茨海默病（AD）的病理生理过程；② 支持这一假设的证据包括AD患者血液和脑部LPS水平升高、AD风险因素会增加LPS水平或反应、LPS能诱导Aβ表达、聚集、炎症和神经毒性、以及LPS会诱导TAU磷酸化、聚集和扩散；③ 相关证据还发现在AD小鼠模型中，血液中的LPS能导致突触、神经元丧失和记忆力下降，且在人类中引起认知功能障碍；④ 如果LPS内毒素假设成立，治疗方法可能包括：减少感染、改变肠道微生物组、减少肠道渗漏、降低血液中的LPS含量或阻断LPS引起的反应。 【原文信息】 The endotoxin hypothesis of Alzheimer's disease 2024-04-01 , doi: 10.1186/s13024-024-00722-y 国内团队：混合益生菌可改善小鼠阿尔茨海默病样认知障碍 Brain Behavior and Immunity——[15.1] ① 上海交通大学医学院附属瑞金医院汤荟冬团队发现多株益生菌治疗能显著改善快速老化模型小鼠（SAMP8）的阿尔茨海默病样认知障碍和病理变化；② SAMP8小鼠经过两种不同复配益生菌治疗后，可显著提升认知能力；③ 益生菌治疗能调节血清短链脂肪酸（如戊酸、异戊酸和己酸）的浓度，且对肠道菌群的α多样性指数无显著影响，但能显著改变特定菌属的相对丰度；④ 混合益生菌治疗能显著减少SAMP8小鼠的神经损伤、Aβ和Tau蛋白病理以及脑部的神经炎症；⑤ 转录组分析揭示益生菌治疗能逆转SAMP8小鼠AKT/GSK-3β通路的磷酸化改变。 【原文信息】 Multi-strain probiotics ameliorates Alzheimer's-like cognitive impairment and pathological changes through the AKT/GSK-3β pathway in senescence-accelerated mouse prone 8 mice 2024-03-26 , doi: 10.1016/j.bbi.2024.03.031 粪菌移植可改善早期帕金森病 EClinicalMedicine——[15.1] ① 开展了一项为期12个月的单中心随机、双盲、安慰剂对照试验，探讨了粪菌移植（FMT）对早期帕金森病（PD）患者的安全性和疗效；② 共纳入46名PD患者分为健康供体组和安慰剂组，接受健康供体粪便移植的PD患者的运动评分平均改善了5.8分，安慰剂组的运动评分平均改善了2.7分；③ 除了暂时的腹部不适外，两组间未观察到其他严重不良事件；④ 本研究表明单次FMT对早期PD患者的运动症状产生了轻微但持久的有益影响，未来仍需在不同疾病阶段的更大患者群中进一步探索。 【原文信息】 Safety and efficacy of faecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT): a double-blind, placebo-controlled, randomised, phase 2 trial 2024-03-27 , doi: 10.1016/j.eclinm.2024.102563 国内团队：人工智能+肠道微环境，助力帕金森病早期诊断 Advanced Science——[15.1] ① 电子科技大学缪养宝团队将人工智能与尖端成像技术和肠道微环境相结合，开发了一种强大的高精度预测帕金森病（PD）的工具；② 这种人工智能引导成像传感器采用耐酸、发光的铕金属有机框架（Eu-MOF），具有精确的孔径和Au-适配体纳米颗粒复合物，用于非侵入性PD监测和诊断；③ 小鼠实验证明，在恶劣的胃肠道条件下，Eu-MOF可以有效地包裹和保护适配体，并且在小鼠肠道中α-Syn存在的情况下，Eu-MOF的荧光信号会被激活，其强度随着适配体/α-Syn复合物释放量的增加而增加；④ 人工智能的集成赋予了PD各个阶段的预测精度，准确率超过98%；⑤ 该研究展示了使用人工智能和先进传感器来监测和预测各种疾病和健康状况的潜力。 【原文信息】 Artificial Intelligence-Guided Gut-Microenvironment-Triggered Imaging Sensor Reveals Potential Indicators of Parkinson's Disease 2024-04-03 , doi: 10.1002/advs.202307819 国内团队：多组学揭秘长寿老人的肠-脑轴 Gut Microbes——[12.2] ① 中南大学湘雅医院沈璐、赵志祥及团队通过多组学分析揭示了肠-脑轴在长寿中的作用；② 纳入83例平均年龄为94岁的长寿人群和81例与长寿人群共同居住且平均年龄为64岁的家属进行粪便多组学检测，发现与对照家属相比，长寿老人的肠道中有438种显著不同的代谢物，其中神经活性化合物和抗炎物质较为丰富；③ 宏基因组数据揭示长寿老人肠道中丰富的神经活性代谢物与特定的肠道菌群密切相关；④ 改变的肠道菌群和代谢物与长寿老人大脑连接性增强有关，尤其是在左侧背外侧前额叶皮层-左前运动皮层、左侧背外侧前额叶皮层-右主运动区、右下额叶回-右主运动区之间；⑤ 潜在有益的肠道菌群可以通过合成神经活性化合物和增强大脑功能连接来间接改善认知。 【原文信息】 Integrated analysis of gut metabolome, microbiome, and brain function reveal the role of gut-brain axis in longevity 2024-03-28 , doi: 10.1080/19490976.2024.2331434 国内团队：微塑料影响肠道，损害造血干细胞 Cell Discovery——[33.5] ① 浙江大学钱鹏旭、黄河团队揭示了微塑料（MPs）通过破坏肠道菌群-次黄嘌呤-Wnt信号轴以抑制造血干细胞（HSCs）自我更新的机制，对临床HSCs移植具有重要意义；② 在长期摄入MPs的小鼠模型中，MPs可严重损害造血系统，降低HSCs的自我更新和重建能力；③ 机制上，MPs并不直接杀死HSCs，而是破坏肠道结构和通透性，导致肠道中Rikenellaceae和次黄嘌呤丰度降低，进而抑制骨髓HSCs中的HPRT-Wnt信号传导；④ 通过补充Rikenellaceae或次黄嘌呤及在体外培养系统中处理WNT10A，可显著恢复MPs诱导的HSCs缺陷；⑤ 在接受健康供体HSCs移植的患者队列中，患者的生存时间与供体粪便和血液中的MPs水平呈负相关，与Rikenellaceae和次黄嘌呤的丰度呈正相关。 【原文信息】 Microplastics dampen the self-renewal of hematopoietic stem cells by disrupting the gut microbiota-hypoxanthine-Wnt axis 2024-03-29 , doi: 10.1038/s41421-024-00665-0 性别确认激素疗法通过肠道菌群影响雄性小鼠的骨骼成熟 Journal of Clinical Investigation——[15.9] ① 性别确认激素疗法（GAHT）通常被开处给跨性别青少年以缓解性别焦虑，这项研究探究了GAHT对不断发育的骨骼的影响；② GAHT通过增加年轻雄性小鼠的骨形成来改善骨小梁结构，并不影响雌性小鼠；③ GAHT改变雄性和雌性小鼠的肠道微生物组成，FMT显示GAHT塑造的雄性肠道菌群可移植并调节其他雄性小鼠的骨骼结构，而雌性小鼠没有这种现象；④ 两种拟杆菌对GAHT在雄性小鼠的骨骼效应具有重要贡献，补充两种拟杆菌可再现GAHT对骨骼的影响，拟杆菌可扩大肠道中Treg亚群，即GAHT扩大了雄性小鼠的肠道调节性T细胞（Tregs）并刺激它们迁移到骨髓（BM），影响骨骼形成过程；⑤ 药理学阻断Treg细胞扩张可抑制GAHT诱导的骨骼新陈代谢。⑥ 在雄性小鼠中，GAHT通过微生物组介导效应促进Treg扩张，从而刺激骨骼形成并改善骨小梁结构，而在雌性小鼠中，GAHT既不改善也不损害梁状结构。 【原文信息】 Gender affirming hormone therapy preserves skeletal maturation in young mice via the gut microbiome 2024-03-26 , doi: 10.1172/JCI175410 修复肠道CFTR或调节菌群或可缓解囊性纤维化相关肝病 Journal of Hepatology——[25.7] ① 本研究揭示了肠道菌群失调在小鼠囊性纤维化相关肝病（CFLD）发病机制中的重要作用，并指出修复肠道囊性纤维化跨膜传导调节因子（CFTR）或调节菌群或可预防或减轻肝病；② CFTR-KO小鼠的肝脏表现出管状增生和门脉区炎症、肝脏中中性粒细胞、巨噬细胞和T细胞增多，且炎症和病原体介导的免疫通路激活，而肠道修复（CFTR-KO-GC）小鼠的肝脏未见明显病理变化；③ CFTR-KO小鼠中肠道菌群失调，肠杆菌科和肠球菌属富集，肠道通透性增加且粘膜具有炎症，而这些现象在CFTR-KO-GC小鼠中未观察到；④ 抗生素治疗可改善CFTR-KO小鼠的肠道通透性和肝脏炎症；⑤ CFTR-KO小鼠群菌移植到无菌WT小鼠无法导致菌群失调或肝脏病理变化，即肠道CFTR缺陷维持致病菌群及炎症环境并改变肠道通透性。 【原文信息】 Prominent role of gut dysbiosis in the pathogenesis of cystic fibrosis-related liver disease in mice 2024-03-28 , doi: 10.1016/j.jhep.2024.03.041 国内团队：肠道菌群外泌体影响精子生成新机制 Advanced Science——[15.1] ① 吉林大学李纯锦、周虚及团队最新研究揭示了肠道菌群失调导致的小鼠精子受损的分子机制，强调了肠源性外泌体在“肠-睾丸”轴中的重要作用；② 通过抗生素干预和粪菌移植实验表明肠道菌群失调改变小鼠循环外泌体中的miRNA表达谱，进而损害精子产生；③ 睾丸组织单细胞测序结果表明外泌体通过抑制减数分裂损害精子发生；④ 肠源性循环外泌体中miR-211-5p的异常上调抑制了睾丸中特异性减数分裂相关蛋白Meioc的表达，从而干扰了减数分裂过程，导致精子生成受损。 【原文信息】 Gut-Derived Exosomes Mediate the Microbiota Dysbiosis-Induced Spermatogenesis Impairment by Targeting Meioc in Mice 2024-03-25 , doi: 10.1002/advs.202310110 益普生「兰瑞肽」在中国获批新适应证，治疗罕见病 ① 4月3日，益普生（Ipsen）宣布其药物醋酸兰瑞肽缓释注射液（预充式）在中国获批新适应证；② 适应证包括：用于不可切除、局部晚期或转移性胃肠胰神经内分泌瘤（GEP-NETs）成人患者，以改善无进展生存期（PFS），以及用于类癌综合征成人患者，以减少短效生长抑素类似物应急治疗频率；③ 该药物此前已于2019年在中国获批用于治疗肢端肥大症；④ GEP-NETs已经被纳入中国《第二批罕见病目录》，兰瑞肽能显著延长患者PFS达38.5个月，降低疾病复发风险53%；⑤ 在针对中国GEP-NETs患者的注册研究（PALACE）中，兰瑞肽显示出积极结果。 【原文信息】 针对这种罕见病，益普生「兰瑞肽」在中国获批新适应症 2024-04-05 , 医药观澜 Infinant Health提交INF108治疗NEC孤儿药物资格认定 ① 4月2日，Infinant Health公司宣布已向FDA提交了INF108一项孤儿药资格认定（ODD）申请；② 活菌药INF108有效成分为一株长双歧杆菌婴儿亚种 ，旨在通过改善婴儿肠道菌群来预防早产儿坏死性结肠炎（NEC）；③ NEC常见于早产儿，目前病因尚未清晰，有证据表明补充肠道有益菌群可改善病情；④ 目前，Infinant Health公司已经获得了比尔及梅琳达·盖茨基金会、强生和嘉吉等头部企业或基金品牌的资助。 【原文信息】 Infinant Health Announces Submission of Orphan Drug Designation Application 2024-04-02 , pr newswire 康巴茶品牌Momo Kombucha完成100万英镑融资 ① 近日，英国康巴茶品牌Momo Kombucha宣布完成了100万英镑（约合人民币913万元）融资，资金来自其现有股东人员；② Momo Kombucha公司计划利用这笔资金搬迁至更大的工厂并扩大产能，以应对日益增长的肠道健康饮品需求；③ 据The Grocer报道，英国康巴茶市场规模达到1930万英镑，康巴茶在美国、澳大利亚的市场规模也在急剧上升；④ 目前，Momo Kombucha公司在英国布局的销售网点达到1000个，并且目标在2026年实现1000万英镑的收入。 【原文信息】 Momo Kombucha raises £1m to keep up with gut health demand 2024-04-03 , Thegrocer 蛋白棒制造商Aloha获得6800万美元融资 ① 近日，蛋白棒生产商Aloha宣布，获得了Semcap Food&Nutrition的6800万美元（约合人民4.92亿元）投资；② Aloha专注于生产具有健康功效的高蛋白能量棒，每块蛋白棒含有蛋白14g，并且其原料来源注重可持续性；③ 自2017年重组以来，Aloha在电商领域取得了巨大成功，在Whole Foods等商超渠道也获得了增长；④ 今年，Aloha销售额预计将达到1亿美元。 【原文信息】 Protein bar maker Aloha gets $68M from venture fund 2024-04-02 , Fooddive 健合集团营养保健食品中试车间顺利落成 ① 4月3日，健合集团在中国广州科学城投资建造的首个中试规模生产车间——健合集团营养保健食品中试车间正式落成；② 中试车间的建立将加强健合集团在营养保健食品研发创新领域的能力，有助于产品快速投产并满足消费者需求；③ 营养保健食品中试车间占地面积超1000平方米，配备了压片机、条包机等主要设备，有助于提升技术创新能力；④ 健合集团将继续推动营养保健食品的研发创新，探索“产学研”一体的发展模式，为消费者提供更优质的营养解决方案。 【原文信息】 健合集团营养保健食品中试车间顺利落成，助力科研+产能双擎驱动 2024-04-03 , 新华报业网 感谢本期日报的审核者：mildbreeze，九卿臣，RZN，圆圈儿，章台柳，617，Richard 点击阅读过去10天的日报： 0405 | 高分Cell子刊：中国农大团队详解后生元 0404 | 顶刊双发：肠菌相关神经发育和肠道免疫研究均有新发现 0403 | 今日Cell肠道研究双发：代谢胆固醇的肠菌+肠炎细胞图谱 0402 | 保肠护关节：高分研究揭示抵御关节炎的肠道因子 0401 | 3月，最值得关注的35篇肠道健康要闻！ 0331 | 聚焦特殊人群：老年人和孕妈妈的饮食新知 0330 | Akk菌或是免疫性肾病帮凶？Science子刊揭示机制 0329 | 33页综述纵论：超加工食品健康转型的新策略 0328 | Science子刊：锁定肠道中让病毒逃脱免疫的"避风港" 0327 | 10文聚焦菌群-肠-脑轴研究新进展

- Based on topline results from the Phase 3 PHOENIX trial of AMX0035 in ALS, Amylyx has started a process with the FDA and Health Canada of voluntarily discontinuing the marketing authorizations for RELYVRIO/ALBRIOZA - RELYVRIO/ALBRIOZA will no longer be available for new patients as of today; Patients currently on therapy in the U.S. and Canada who, in consultation with their physician, wish to continue can be transitioned to a free drug program; PHOENIX Open Label Extension is ongoing - Amylyx continues to advance AMX0035 in Wolfram syndrome and in progressive supranuclear palsy (PSP), and AMX0114 in ALS - Interim data from the Phase 2 HELIOS trial of AMX0035 for the treatment of Wolfram syndrome are expected this month and will be presented during a webcast on April 10, 2024 - Restructuring plan reduces workforce by approximately 70% to focus resources on key clinical and preclinical programs and extends expected cash runway into 2026, through anticipated data readouts for AMX0035 in Wolfram syndrome and PSP, and AMX0114 in ALS CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Amylyx Pharmaceuticals, Inc. (NASDAQ: AMLX) (“Amylyx” or the “Company”) today announced the Company has started a process with the U.S. Food and Drug Administration (FDA) and Health Canada to voluntarily discontinue the marketing authorizations for RELYVRIO®/ALBRIOZA™ (sodium phenylbutyrate and taurursodiol [also known as ursodoxicoltaurine]; also known as AMX0035) and remove the product from the market in the U.S. and Canada based on topline results from the Phase 3 PHOENIX trial. RELYVRIO/ALBRIOZA will no longer be available for new patients as of today. Patients currently on therapy in the U.S. and Canada who, in consultation with their physician, wish to stay on treatment can be transitioned to a free drug program. “While this is a difficult moment for the ALS community, we reached this path forward in partnership with the stakeholders who will be impacted and in line with our steadfast commitment to people living with ALS and other neurodegenerative diseases. The decision to remove RELYVRIO/ALBRIOZA from the market and provide therapy free of charge for those who wish to continue was informed by the PHOENIX trial results, engagement with regulatory authorities, and discussions with the ALS community. Thank you to each and every person who shared feedback with us and continues to support our commitment to the ALS community,” said Joshua Cohen and Justin Klee, Co-CEOs of Amylyx. Amylyx will continue to evaluate and share learnings from PHOENIX to help inform future ALS research. At this time, Amylyx intends to continue to collect available data on survival at the encouragement of ALS specialists. The PHOENIX Open Label Extension (OLE) is ongoing. Topline data from PHOENIX will be presented at the American Academy of Neurology (AAN) Annual Meeting in Denver and online, taking place April 13-18, 2024. The presentation is scheduled to occur on April 16, 2024, during the Clinical Trials Plenary Session (9:15 a.m. – 11:30 a.m. MT) and will be made available on the “Publications and Presentations” section of the Company’s website following the conclusion of the presentation. As part of the Company’s purpose to discover and develop innovative new treatment options for neurodegenerative diseases, Amylyx continues to advance two key programs investigating its lead asset AMX0035 in Wolfram syndrome and progressive supranuclear palsy (PSP), and AMX0114, an antisense oligonucleotide targeting calpain-2, in ALS. “Our pipeline is supported by compelling clinical and preclinical science demonstrating the potential of AMX0035 and AMX0114 in neurodegenerative diseases. AMX0035 was designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. We are investigating AMX0035 in diseases where these two pathways are implicated, which includes Wolfram syndrome and progressive supranuclear palsy,” said Camille L. Bedrosian, MD, Chief Medical Officer of Amylyx. “We look forward to presenting interim data from our Phase 2 HELIOS study of AMX0035 in Wolfram syndrome, a rare, genetic, fatal neurodegenerative disease with no FDA-approved treatment options, later this month. In addition, our Phase 3 ORION study remains ongoing to evaluate AMX0035 for the treatment of progressive supranuclear palsy, a rare neurodegenerative disorder characterized as a tauopathy. We continue to plan for an interim analysis to evaluate the data from ORION that is now expected in mid-2025.” Dr. Bedrosian continued, “We also remain focused on ALS and believe AMX0114 has strong potential for the treatment of ALS and other diseases. Calpain-2 is considered an essential protein in the process of axonal degeneration and has been repeatedly linked to neurofilament biology in published studies. In our preclinical studies of AMX0114 and in multiple independent published studies, inhibition of calpain-2 has reduced cell death and degeneration and decreased neurofilament levels. We expect to initiate a clinical trial studying AMX0114 in ALS in the second half of this year.” Amylyx also announced a restructuring to focus the Company’s financial resources on upcoming clinical milestones. The Company will reduce its workforce by approximately 70% and decrease external financial commitments outside of its priority areas. With these changes, Amylyx expects to have cash runway into 2026, which will allow the organization to deliver on key upcoming milestones, including data readouts from HELIOS (AMX0035 in Wolfram syndrome), ORION (AMX0035 in PSP), and its planned trial of AMX0114 in ALS. “We are so thankful and grateful to our Amylyx team for their contributions and steadfast dedication,” said Cohen and Klee. “Together, the work we have accomplished across the world has helped build a vital foundation to achieve our mission of one day ending the suffering caused by neurodegenerative diseases, which continue to have critical, unaddressed needs.” HELIOS Interim Data in Wolfram Syndrome Investor Webcast Details Amylyx will host a virtual webcast with Dr. Fumihiko Urano, Principal Investigator of the Phase 2 HELIOS clinical trial in Wolfram syndrome and Professor Medicine in the Division of Endocrinology, Metabolism & Lipid Research at Washington University School of Medicine, to discuss interim HELIOS data on April 10, 2024, at 1:30 p.m. ET. A live webcast of the presentation can be accessed under “Events and Presentations” in the Investor section of the Company’s website, , and will be available for replay for 90 days following the event. About AMX0035 AMX0035 is an oral, fixed-dose combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO; also known as ursodoxicoltaurine outside of the U.S.). AMX0035 was designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum (ER) stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration. We believe that our proprietary combination of PB and TURSO and their complementary mechanisms of action will allow us to synergistically target abnormal cell death to better prevent neurodegeneration than treatment targeted at either mechanism of action alone. AMX0035 is being studied as a potential treatment for Wolfram syndrome and progressive supranuclear palsy, two neurodegenerative diseases. About AMX0114 AMX0114 is an antisense oligonucleotide designed to target the gene encoding calpain-2, a key contributor to the axonal (Wallerian) degeneration pathway. Axonal degeneration has been recognized as an important early contributor to the clinical presentation and pathogenesis of ALS and other neurodegenerative diseases. Calpain-2 has been implicated in the pathogenesis of ALS based on findings of elevated levels of calpain-2 and its cleavage products in postmortem ALS tissue, therapeutic benefit of calpain-2 modulation in animal models of ALS, and the role of calpain-2 in cleaving neurofilament, a broadly researched biomarker in ALS. Preclinical studies completed to date have shown that AMX0114 achieves potent, dose-dependent, and durable knockdown of CAPN2 mRNA expression and calpain-2 protein levels in human motor neurons. Moreover, in preclinical efficacy studies, treatment with AMX0114 reduced extracellular neurofilament light chain levels following neurotoxic insult in induced pluripotent stem cell (iPSC)-derived human motor neurons, and improved survival of iPSC-derived human motor neurons harboring ALS-linked, pathogenic TDP-43 mutations. About ALS Amyotrophic lateral sclerosis (ALS, also known as motor neuron disease) is a relentlessly progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and eventually, death. More than 90% of people with ALS have sporadic disease, showing no clear family history. ALS affects around 30,000 people in the U.S., and more than 30,000 people are estimated to be living with ALS in Europe (European Union and the United Kingdom). People living with ALS have a median survival of approximately two years from diagnosis. About the HELIOS Trial The HELIOS trial (NCT05676034) is a 12-participant, open-label, proof of biology, Phase 2 trial designed to study the effect of AMX0035 on safety and tolerability, and various measures of endocrinological, neurological, and ophthalmologic function in adult participants living with Wolfram syndrome. About Wolfram Syndrome Wolfram syndrome is an autosomal recessive neurodegenerative disease characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. Genetic and experimental evidence suggests that endoplasmic reticulum (ER) dysfunction is a critical pathogenic component of Wolfram syndrome. The prognosis of Wolfram syndrome is poor, and many people with the disease die prematurely with severe neurological disabilities. About the ORION Trial The ORION trial (NCT06122662) is a global, randomized, double-blind, placebo-controlled Phase 3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with progressive supranuclear palsy (PSP). The ORION Phase 3 trial was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations. About PSP Progressive supranuclear palsy (PSP) is a sporadic, rare, and adult-onset neurodegenerative disorder that affects walking and balance, eye movement, swallowing, and speech. People living with PSP have a life expectancy of six to eight years after initial diagnosis, and its epidemiology is similar to that of amyotrophic lateral sclerosis (ALS). PSP typically begins in late-middle age and rapidly progresses over time. The disease affects approximately seven in 100,000 people worldwide, and there are currently no disease-modifying therapies approved for the treatment of PSP. PSP is characterized by abnormal tau inclusions and is consequently also known as a tauopathy. Similar to other neurodegenerative diseases, pathophysiologic changes underlying PSP are multifactorial, with several genetic and environmental factors likely contributing to tau dysfunction and aggregation. Multiple pathways, including genetic mutations, endoplasmic reticulum (ER) stress, and the activation of unfolded protein response, mitochondrial dysfunction, and neuroinflammation have been implicated as contributors to tau dysfunction and aggregation. About Amylyx Pharmaceuticals Amylyx Pharmaceuticals, Inc. is committed to supporting and creating more moments for the neurodegenerative disease community through the discovery and development of innovative new treatments. Amylyx is headquartered in Cambridge, Massachusetts. For more information, visit amylyx.com and follow us on LinkedIn and X, (formerly Twitter). For investors, please visit investors.amylyx.com. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, Amylyx’ expectations regarding: interactions with regulatory authorities; the availability of RELYVRIO/ALBRIOZA for patients currently taking RELYVRIO/ALBRIOZA; the timing and significance of learnings from the PHOENIX trial, the PHOENIX survival analysis and the Open Label Extension; the continued evaluation of AMX0035 in other neurodegenerative diseases, including the timing for expected data readouts in the ORION and HELIOS studies; the potential for AMX0114 as a treatment for ALS and the planned initiation of a trial evaluating AMX0114 in ALS; and the impact of resource-conserving measures on extending the Company's cash runway, including the restructuring plan. Any forward-looking statements in this press release are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include the risks and uncertainties set forth in Amylyx’ United States Securities and Exchange Commission (SEC) filings, including Amylyx’ Annual Report on Form 10-K for the year ended December 31, 2023, and subsequent filings with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Amylyx undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

A traumatic brain injury (TBI) can quadruple your risk for developing dementia and increase your chances of developing neurodegenerative diseases such as ALS. In a new study scientists use lab-grown human brain structures known as organoids to offer insights into why this is the case and how to mitigate the risk. A traumatic brain injury (TBI) can quadruple your risk for developing dementia and increase your chances of developing neurodegenerative diseases such as ALS. In a new study published in Cell Stem Cell, USC scientists use lab-grown human brain structures known as organoids to offer insights into why this is the case and how to mitigate the risk. In the study, former postdoc Jesse Lai and PhD student Joshua Berlind from the USC Stem Cell laboratory of Justin Ichida used human patient-derived stem cells to grow rudimentary brain structures known as organoids in the lab. They then injured these organoids with high-intensity ultrasound waves. The injured organoids showed some of the same features seen in TBI patients, including nerve cell death and pathological changes in tau proteins, as well as in a protein called TDP-43. The scientists found that the pathological changes in TDP-43 were more prevalent in organoids derived from patients with ALS or frontotemporal dementia, making their nerve cells more suspectable to dysfunction and death following injury. This suggests that TBI might increase the risk of developing these diseases even more for patients with a genetic predisposition. The worst injuries were sustained by nerve cells that share information -- called excitatory neurons -- located in the deep layers of the organoids. In their search for ways to protect these neurons against the effects of TBI, the scientists identified a gene called KCNJ2, which contains instructions for making channels that selectively allow potassium to pass through the cell membrane, helping to enable muscle contraction and relaxation. Inhibiting this gene had a protective effect on organoids derived from patients with and without ALS, as well as on mice, following a TBI. "Targeting KCNJ2 may reduce the death of nerve cells after TBI," said Ichida, who is the John Douglas French Alzheimer's Foundation Associate Professor of Stem Cell Biology and Regenerative Medicine at USC, and a principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. "This could have potential as either a post-injury treatment or as a prophylactic for athletes and others at high risk for TBI." About the authors and the study Co-corresponding author Ichida is also a co-founder of AcuraStem and Modulo Bio, a Scientific Advisory Board (SAB) member at Spinogenix and Vesalius Therapeutics, and an employee in the Research and Early Development group at BioMarin Pharmaceutical. Co-corresponding author Lai and co-author Violeta Yu were both employees of Amgen during the study, and currently work at Dewpoint Therapeutics. Named companies were not involved in this research project. First author Berlind is a PhD student in the Ichida Lab. Additional co-authors are Gabriella Fricklas, Cecilia Lie, Jean-Paul Urenda, Kelsey Lam, Naomi Sta Maria, Russell Jacobs, and Zhen Zhao from USC. Fifty percent of the work was supported by federal funding from the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (grant F31NS117075), NINDS (grant R01 1R01NS097850-01), and the Department of Defense (grant 12907280). The project was also privately funded by an Amgen postdoctoral fellowship, the New York Stem Cell Foundation, the Tau Consortium, the Harrington Discovery Institute, the Alzheimer's Drug Discovery Foundation, the Association for Frontotemporal Dementia, and the John Douglas French Alzheimer's Foundation.