SLC22A17

03月21日的《热心肠日报》，我们解读了 15 篇文献，关注：具核梭杆菌，宿主-菌群互作，肠道芯片，方法学，医疗器械，消化系统疾病，肠癌，乳糜泻，GvHD，联合利华，Verb Biotics，Inventiva，巧捷力，Cauldron。 该篇日报由R·AI辅助创作生成，人工审核校对。 Nature：促肠癌的具核梭杆菌亚种分支 Nature——[64.8] ① 具核梭杆菌（ Fn ）是一种口腔菌，但在结直肠癌（CRC）中富集并可促癌，这项研究对人类 Fn 菌株进行大规模比较基因组学分析，发现 Fn 动物亚种（ Fna ）中的1个分支 Fna C2 是促CRC的主要元凶；② 该研究生成了135个 Fn 菌株的完整基因组（包括无癌个体的口腔菌株和CRC患者的肿瘤菌株），鉴定出CRC中富集的483个遗传因子；③ 肿瘤菌株主要属于 Fna ， Fna 又可分为 Fna C1 和 Fna C2 两个分支，只有 Fna C2 在CRC肿瘤中富集；④ 确定了195个 Fna C2 相关遗传因子，可能赋予其更强的细胞侵袭性（如 fap2 ）、代谢能力（如 eut 和 pdu 操纵子）和胃肠道定植能力（如抵抗胃酸）；⑤ Fna C2 显著增加模型小鼠的肠道腺瘤数量，改变肠道代谢特征，增加氧化应激；⑥ CRC患者肿瘤组织和大队列粪便菌群分析，进一步证实了 Fna C2 与CRC的关系；⑦ 总之， Fna C2 是 Fn 的一个高毒性亚群，应成为CRC机理研究和药物研发的主要关注点。 【原文信息】 A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche 2024-03-20 , doi: 10.1038/s41586-024-07182-w Nature：新方法！大规模揭示人体与菌群的跨界互作连接 Nature——[64.8] ① 微生物可通过与宿主的外蛋白（指胞外蛋白和分泌蛋白）互作来促进定植和影响宿主生物学，本研究开发了一种新技术BASEHIT，首次在蛋白质组水平上大规模评估了人类外蛋白组与微生物组之间的相互作用；② 检测519个人类相关细菌菌株和3324种人类外蛋白之间的170多万种潜在互作，揭示了一个由383个菌株和600多种宿主蛋白组成的广泛互作网络，包括数千个新发现的宿主-微生物互作；③ 该网络中的特定结合模式暗示了潜在的生物学逻辑，例如同物种菌株表现出共享的外蛋白结合模式，而特定组织的分离菌株则与组织特异性外蛋白结合；④ 还发现了数十种独特的且多为菌株特异性的互作，在生态位定植、组织重塑和免疫调节中可能发挥作用，具有不同宿主互作特征的菌株在与宿主细胞的互作和对宿主免疫系统的影响上存在差异；⑤ 该研究揭示了一个之前未被探索的宿主-菌群分子层面互作景观，可能是菌群对人类健康和疾病产生因果效应的基础。 【原文信息】 A host–microbiota interactome reveals extensive transkingdom connectivity 2024-03-20 , doi: 10.1038/s41586-024-07162-0 肠道芯片模型研究白色念珠菌与宿主互作及抗真菌药物疗效 Biomaterials——[14] ① 本研究使用3D肠道芯片模型研究白色念珠菌与宿主之间的相互作用及抗真菌药物卡泊芬净的疗效；② 微生物学和基于图像的分析可量化真菌侵袭和跨越上皮屏障的感染过程，并获得有关真菌微菌落形态及其与组织的关联；③ 白色念珠菌微菌落通过破坏顶端细胞间的接触引起上皮组织损伤和炎症；④ 卡泊芬净治疗可有效减少野生型菌株感染期间的真菌生物量并显著改变微菌落形态，但对棘白菌素耐药的临床分离株效果有限；⑤ 本研究表明3D器官芯片模型可用于深入研究病原体与宿主相互作用以及抗菌治疗引起的变化，并揭示了白色念珠菌微菌落对上皮组织的损伤及药物治疗对微菌落形态的显著影响。 【原文信息】 Modeling of intravenous caspofungin administration using an intestine-on-chip reveals altered Candida albicans microcolonies and pathogenicity 2024-03-09 , doi: 10.1016/j.biomaterials.2024.122525 新型肠道芯片：让肠道微生物“无所遁形” Advanced Science——[15.1] ① 本研究开发了一种具有优异成像能力和扩展性的肠道微生物芯片（GMoC），将微生物生长和运动、微生物群落内的相互作用以及它们对肠道的个体和集体影响可视化；② 该芯片采用Caco-2细胞衍生的可重复的三维分层肠道上皮（µGut），成功模拟了肠道环境，包括复杂的肠道结构、功能和细胞复杂性，为肠道微生物提供了一个生理相关的环境；③ 将产肠毒素的脆弱拟杆菌（ETBF）引入GMoC，可观察到ETBF的致病行为，导致µGut破坏和促肿瘤信号的激活；④ 使用乳杆菌预处理µGut可以有效防止ETBF引起的肠道病理过程，通过竞争性介导的定植抵抗保持µGut的健康状态；⑤ GMoC为探索肠道微生物在病理发生中的未知角色及基于微生物的治疗开发提供了宝贵的工具。 【原文信息】 Dissecting Gut-Microbial Community Interactions using a Gut Microbiome-on-a-Chip 2024-02-27 , doi: 10.1002/advs.202302113 微生物组功能分析新工具：兼顾速度和详尽性的Astral质谱仪 Microbiome——[15.5] ① 微生物组因其成分多样、动态变化、功能复杂，对分析带来挑战，目前的微生物组蛋白质谱分析方法存在数据覆盖度较低、分析速度较慢的限制，本研究通过结合数据依赖性（DDA）和数据独立性分析模式（DIA），基于Astral质谱仪实现了对高复杂样本的快速、高覆盖度分析；② 基于两种纯菌株培养物和人类粪便样品构建了加标MetaP参比样品，使用Astral质谱仪DDA模式获得9门、44属和56种蛋白质谱数据，其覆盖度优于Exploris质谱仪；③ 选择丰度高的48个种构建了DB48蛋白质序列数据库，基于DIA模式，实现了超过122000个独特肽段和38000个蛋白质组的覆盖，这一成果显著超越了当前最先进的宏蛋白组学方法；④ 基于KEGG数据库对鉴定所得的71%的微生物蛋白和89%的宿主蛋白进行了KO功能注释，低丰度蛋白富集的KO通路也表现出相当的覆盖度，其中两种纯菌株也有65%和62%的蛋白质被注释，获得的代谢特征与先前报道一致。 【原文信息】 The astounding exhaustiveness and speed of the Astral mass analyzer for highly complex samples is a quantum leap in the functional analysis of microbiomes 2024-03-07 , doi: 10.1186/s40168-024-01766-4 华科大Nature子刊：磁驱动多功能胶囊-医疗应用的新利器 Nature Communications——[16.6] ① 华中科技大学李亮和曹全梁作为共同通讯作者发表研究，开发出一种小型磁驱动胶囊，通过磁性软阀的灵活开合可实现药物释放和采样的功能整合，具有主动靶向输运、定点采样与多重给药等功能；② 基于多频响应控制的磁激励策略，有效实现胶囊全局运动和局部响应的解耦调节；③ 通过理想模型实验、动物体外器官模型实验、动物体内实验等功能验证评估，展示出磁性胶囊在生物医学领域的多功能性和多种潜在应用。 【原文信息】 Magnetically driven capsules with multimodal response and multifunctionality for biomedical applications 2024-02-29 , doi: 10.1038/s41467-024-46046-9 活检蛋白质组评分在乳糜泻黏膜重塑量化中的应用 Gastroenterology——[29.4] ① 本研究通过将乳糜泻（CeD）中的活检蛋白质组数据转化为数字评分，为无需依赖观察者的乳糜泻黏膜重塑提供了新的量化方法；② 蛋白质组数据通过两种互补的方法转换为数值分数，一种是基于排名的富集分数，另一种是基于机器学习的逻辑回归分数；③ 两种评分方法高度相关，均能反映相同生物途径中的蛋白质组变化；④ 蛋白质组评分与绒毛长度与隐窝深度比值相关，能够有效评分定位不佳的活检样本；⑤ 活检蛋白质组评分为CeD中黏膜重塑提供了可靠的、不依赖观察者和样本定位的量化指标，可与组织学评估并行实施，易于在临床试验中推广。 【原文信息】 Biopsy proteome scoring to determine mucosal remodeling in celiac disease 2024-03-09 , doi: 10.1053/j.gastro.2024.03.006 Science子刊：重组LCN2或可治疗急性移植物抗宿主病 Science Translational Medicine——[17.1] ① 本研究通过单细胞RNA测序技术，首次在急性移植物抗宿主病（aGVHD）小鼠肠道中鉴定出一种表达lipocalin-2（LCN2）的中性粒细胞群；② 转移过表达LCN2的中性粒细胞或使用重组LCN2治疗可减轻aGVHD的严重程度，而缺乏上皮或造血细胞的LCN2会增加aGVHD的严重程度并导致菌群改变；③ 机制上，LCN2通过受体SLC22A17在巨噬细胞中诱导胰岛素样生长因子1受体信号传导，增加IL-10产生并降低MHCII表达；④ 转移经LCN2预处理的巨噬细胞可减轻aGVHD的严重程度，但不减少移植物抗白血病效应；⑤ LCN2在多个aGVHD患者队列的肠道活检中与IL-10表达相关，且在人类巨噬细胞中诱导IGF-1R信号传导；⑥ 本研究揭示了LCN2在调节肠道免疫反应中的关键作用，为aGVHD提供了潜在的治疗方法。 【原文信息】 Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease 2024-02-21 , doi: 10.1126/scitranslmed.adi1501 自主AI VS AI辅助人类进行光学诊断结肠息肉 Gastroenterology——[29.4] ① 本研究通过随机对照试验，比较了完全自主的人工智能（AI）与AI辅助人类（AI-H）在结直肠息肉光学诊断中的性能，发现自主AI在光学诊断的准确性上不逊色于内窥镜医生的诊断，并且在与病理学监测间隔的一致性上表现更佳；② 467名患者被随机分组，自主AI组238名患者共发现158个息肉，AI-H组229名患者共179个息肉，两组的光学诊断准确率分别为77.2%和72.1%，显示两者之间无显著差异；③ 对于高信心诊断，自主AI组和AI-H组的准确率分别为77.2%和75.5%；④ 在与病理学监测间隔的一致性上，自主AI组显著高于AI-H组（91.5% vs 82.1%)，表明其在长期监测策略制定上可能更为准确。 【原文信息】 Autonomous Artificial Intelligence versus AI Assisted Human optical diagnosis of colorectal polyps: A randomized controlled trial 2024-02-06 , doi: 10.1053/j.gastro.2024.01.044 人工智能在胃肠病理学中的作用：最新进展 Clinical Gastroenterology and Hepatology——[12.6] ① 本综述总结了人工智能（AI）在胃肠组织病理学中的潜在应用和可能的挑战；② 过去十年，AI在临床领域取得了显著进展，尤其在胃肠道疾病方面；③ AI技术在病理学数字化数据的积累下，有望在胃肠道病理学领域取得更大突破；④ 对于胃肠病学家或病理学家来说，这无疑是一个激动人心的时刻，AI与数字组织学的结合可能会以一种有利的方式极大地影响病人的诊疗；⑤ 本文概述了AI技术在胃肠道病理学中的几个高影响力例子，但要承认，在商业化之前和广泛采用之前，必须解决诸多限制。 【原文信息】 The Evolving Role of Artificial Intelligence in Gastrointestinal Histopathology: An Update 2023-12-26 , doi: 10.1016/j.cgh.2023.11.044 联合利华宣布剥离冰淇淋业务 ① 3月19日，联合利华宣布剥离旗下冰淇淋业务，该部门拥有Magnum和Ben&Jerry’s等品牌；② 联合利华旨在通过此次业务剥离，专注运营美容与健康、个人护理、家庭护理、营养品四大业务，实现中等个位数的销售增长和利润率改善；③ 拆分后，冰淇淋业务管理团队将拥有运营和财务足够的灵活性来发展业务，包括进一步优化制造和物流网络，发展分销渠道等。④ 业务剥离工作立即开始，预计于2025年底完成；⑤ 此外，联合利华还计划在未来三年内节省约8亿欧元成本（约合人民币62.51亿），影响约7500个工作岗位。 【原文信息】 重磅！联合利华宣布剥离冰淇淋业务 2024-03-19 , FoodTalks Verb Biotics公布肠道健康解决方案Keystone Postbiotic临床前研究数据 ① 3月19日，Verb Biotics公司对外公布了肠道健康产品Keystone Postbiotic的临床前积极数据；② Keystone Postbiotic是一种益生菌发酵燕麦后制成的后生元产品，并且可以与葡萄籽提取物复配以进一步提高其抗氧化性；③ 临床前研究显示，Keystone Postbiotic能显著增加肠道中的有益菌群，增强短链脂肪酸的产生，并调节细胞因子水平以支持免疫反应和改善肠道屏障功能；④ 在人粪便样本中，单独使用Keystone Postbiotic时，双歧杆菌增加50倍以上，Keystone Postbiotic结合葡萄籽提取物使用时，双歧杆菌增加300倍以上。 【原文信息】 Verb Biotics Announces Data from Preclinical Studies to Support Foundational Gut Microbiome Health from Newly Launched Keystone Postbiotic™ 2024-03-19 , PR Newswire Inventiva创新药lanifibranor达2期临床主要终点 ① 近日，Inventiva公司宣布，管线药物lanifibranor在2期临床LEGEND研究中取得良好中期分析结果，达到主要疗效终点；② LEGEND研究旨在评估lanifibranor联用恩格列净治疗代谢功能障碍相关性脂肪性肝炎（MASH）/非酒精性脂肪性肝炎（NASH）和控制不佳的2型糖尿病（T2D）患者的效果；③ 中期分析结果显示，与安慰剂组相比，lanifibranor治疗组和lanifibranor联用恩格列净治疗组的糖化血红蛋白水平显著下降；④ 此外，接受lanifibranor联合恩格列净治疗的患者体重保持稳定，且腹部内脏脂肪与皮下脂肪的比率显著降低；⑤ Lanifibranor是一种口服小分子泛PPAR激动剂，2020年10月获得FDA授予的突破性疗法认定，用于治疗MASH或NASH。 【原文信息】 速递 | 治疗MASH/NASH和2型糖尿病，创新药物达2期试验主要终点 2024-03-20 , 药明康德 手术机器人公司「巧捷力」完成1000万美元A+轮融资 ① 近日，巧捷力医疗机器人完成1000万美元（约合人民币7199万元）的A+轮融资，新加坡家族基金独家完成投资；② 本轮融资将主要用于推进巧捷力医疗机器人的研发进程及临床注册工作；③ 巧捷力专注于自然腔道手术机器人的创新，研发出全球最小全柔性双臂内镜手术机器人，技术水平达到国际领先；④ 目前，巧捷力全柔性内镜手术机器人已正式进入FDA和NMPA的注册审批流程，并全球范围内同步推进产品注册。 【原文信息】 巧捷力完成1000万美元A+轮融资，推进研发和临床注册 2024-03-20 , 动脉网 澳洲精密发酵公司「Cauldron」完成950万澳元融资 ① 3月19日，澳洲精密发酵初创公司Cauldron宣布完成了950万澳元（约合人民币4466万元）的A轮融资，Horizons Ventures领衔了本次投资；② 本轮融资后，Cauldron累计筹集资金达到2000万美元，资金将用于扩展Cauldron的制造平台和建立精密发酵设施网络；③ Cauldron专注于超发酵技术，旨在提升生产效率和降低成本，其技术可应用于食品、饲料、纤维和燃料等多个领域；④ 目前，该公司已成功运行10000升生产系统超过8个月，展示了其技术的连续生产能力和高效性。 【原文信息】 融资超600万美元，澳洲精密发酵公司发力连续超发酵技术，产量可提升5倍 2024-03-19 , 融资超600万美元，澳洲精密发酵公司发力连续超发酵技术，产量可提升5倍 感谢本期日报的审核者：mildbreeze，圆圈儿，RZN，Johnson，九卿臣，章台柳，注册营养师陈彬林，Alex Zhang，Richard 点击阅读过去10天的日报： 0320 | 12页高分综述解析：抗生素扰乱菌群，对宿主代谢有何影响？ 0319 | 今日Cell：国内团队发现新肠道激素，连起肠肝轴胆固醇代谢调控 0318 | NEJM双发：大肠癌无创检测取得新突破 0317 | Cell子刊：多组学+长追踪，深度解析人体菌群动态和与宿主的互作 0316 | 国内团队34页综述详解：用饮食干预对抗疾病 0315 | 顶刊小高潮：王良静等Cell重磅突破，Science三文聚焦肠菌 0314 | 今日Nature：抵御肠道感染，菌群色氨酸代谢物有新招 0313 | 朱书/潘文等Cell子刊新发现：肠菌胆汁酸代谢如何影响大肠癌抗肿瘤免疫？ 0312 | 65分综述详解ILC3：守护肠道健康的重要免疫细胞 0311 | 分析81万人数据：根除幽门螺杆菌，还能防肠癌？

Preeclampsia is a hypertensive disorder of pregnancy and affects about 5% of pregnant women globally, out of whom 0.5% to 1% develop it in the severe form. It is one of the most common complication of pregnancy and a major cause of morbidity, long-term debility, and death among both the baby and the mother. Preeclampsia generally occurs after the 20th week of pregnancy, caused by mixture of elevated blood pressure and protein in the urine (proteinuria). Severe headache, blurring vision, heartburn, and swelling of the face are the common symptoms of preeclampsia. According to a report published by the Center for Maternal and Child Enquiries in the U.K., preeclampsia was ranked as the second most common direct cause of maternal death between 2006 and 2008. In Asia and Africa, one in 10 deaths is associated with pregnancy related hypertension. However, majority of deaths caused by eclampsia or preeclampsia are preventable through proper diagnosis and effective care of the patients. Preeclampsia accounts for about 20% of total maternal deaths and is the third leading cause of maternal mortality in the U.S. Read Report Overview - The preeclampsia diagnostics market can be segmented into test type, instrument, and end-user. Based on test type, the global preeclampsia diagnostics market can be classified into biomarker and immunoassay. The immunoassay (ELISA) segment can be further divided into Elecsys PIGF/sFLT-1, and DELFIA Xpress PlGF kit2. The immunoassay test provides early and specific diagnosis of preeclampsia. The biomarker segment can be further categorized into placental growth factor (PlGF), vascular endothelial growth factor (VEGF), soluble endoglin (sEng), soluble Fms-like tyrosine kinase -1(sFlt-1), pregnancy associated plasma protein-A (PAPP-A), placental protein 13(PP-13), neutrophil gelatinase-associated lipocalin (NGAL), and others. Request Brochure of Report - Based on instrument, the global preeclampsia diagnostics market can be segmented into Victor2 D Instrument, AutoDELFIA immunoassay system for prenatal screening, and others. In terms of end-user, the global preeclampsia diagnostics market can be divided into hospitals, specialty clinics, diagnostics laboratories, research centers, and others. The diagnostics laboratories segment constituted major market share in 2016. The specialty clinics segment is expected to register high growth during the forecast period. Good service provided by the specialty clinics and diagnostics laboratories, and availability of instruments are estimated to propel the market during the forecast period. Other factors that drive the global preeclampsia diagnostics market are rise in prevalence of pregnancy related hypertension and recent developments in diagnostics kits. Request for Analysis of COVID-19 Impact on Preeclampsia Diagnostics Market- Geographically, the global preeclampsia diagnostics market can be segmented into North America, Latin America, Europe, Asia Pacific, and Middle East & Africa. North America is expected to account for high market share of the global preeclampsia diagnostics market, owing to the developments in diagnostic tests and increase in prevalence of pregnancy related diseases in the region. Europe accounted for major market share in 2016, owing to rise in incidence of preeclampsia in the region. Governments of countries in Europe are focused on launching awareness programs for prevention of preeclampsia, and diagnostics and treatment of women suffering from the disease. In 2012, the European Foundation for the Care of Newborn Infants (EFCNI), announced collaboration with PerkinElmer, a global leader focused on improving the health and safety of people and environment. Rise in prevalence of the disease is expected to boost the growth of the preeclampsia diagnostics market during the forecast period. The market in Asia Pacific is expected to register a high CAGR during the forecast period. Rise in demand for newer and advanced diagnostics tools, increase in research and development programs, and participation of governments in creating awareness about the disease are expected to boost the growth of the market in the region during the forecast period. Request for Custom Research - Key players in the global preeclampsia diagnostics market are Roche, DRG INSTRUMENTS GMBH, PerkinElmer Inc., Diabetomics, Inc., Siemens AG, LionsGate Technologies Inc., among others. Roche was the first company that developed immunoassay for diagnosis of preeclampsia. Growing demand for preeclampsia screening due to rise in awareness about the disease is expected to propel the global preeclampsia market during the forecast period. Pre Book Preeclampsia Diagnostics Market Report - About Us Transparency Market Research is a next-generation market intelligence provider, offering fact-based solutions to business leaders, consultants, and strategy professionals. Our reports are single-point solutions for businesses to grow, evolve, and mature. Our real-time data collection methods along with ability to track more than one million high growth niche products are aligned with your aims. The detailed and proprietary statistical models used by our analysts offer insights for making right decision in the shortest span of time. For organizations that require specific but comprehensive information we offer customized solutions through ad hoc reports. These requests are delivered with the perfect combination of right sense of fact-oriented problem solving methodologies and leveraging existing data repositories. TMR believes that unison of solutions for clients-specific problems with right methodology of research is the key to help enterprises reach right decision. Contact Mr. Rohit Bhisey Transparency Market Research State Tower, 90 State Street, Suite 700, Albany NY - 12207 United States USA - Canada Toll Free: 866-552-3453 Email: sales@transparencymarketresearch.com Website:

LA JOLLA, Calif., May 3, 2021 /PRNewswire/ -- Regulus Therapeutics Inc. (Nasdaq: RGLS), a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs (the "Company" or "Regulus"), today announced top-line results from the first cohort of patients with ADPKD in its ongoing Phase 1b clinical trial of RGLS4326. The study is evaluating the safety, pharmacokinetics, and effects on pharmacodynamic biomarkers of multiple doses of RGLS4326 in patients with ADPKD. In the first cohort, nine patients were enrolled and received 1 mg/kg of RGLS4326 subcutaneously every other week for four doses. Safety, pharmacokinetics, and certain disease related biomarkers were evaluated through the course of the study. The biomarkers included: Polycystin 1 (PC1) and Polycystin 2 (PC2) which are the protein products of the PKD1 and PKD2 genes respectively, kidney injury marker 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), as well as urea and creatinine and were chosen to evaluate changes in disease related measures. RGLS4326 was well tolerated by all nine patients with no serious adverse events reported. All reported adverse events were mild and generally transient in nature. Overall, the pharmacokinetic pro RGLS4326 in patients with ADPKD was similar to the pharmacokinetic pro in a prior healthy volunteer study with the following observations: The half-life of RGLS4326 in plasma was slightly longer in patients with impaired renal function and did not exhibit any signs of accumulation in plasma. RGLS4326 plasma concentrations in patients were elevated relative to healthy volunteers with mean plasma AUC levels after the first and fourth dose approximately two-fold higher in patients. Higher plasma exposure is anticipated to lead to higher kidney exposure allowing for potential dose reductions needed to achieve desired kidney exposure. A statistically significant increase in the PC1 biomarker was observed in the first cohort of this study. The mean increase at Day 71 (n=8) compared to baseline was greater than 50% and all patients had double digit increases in PC1 levels with an overall trend showing increasing levels of both PC1 and PC2 over time. Mean PC2 levels increased compared to baseline levels (>20%) however the results did not reach statistical significance. Importantly, at the time of the analysis, mutational status was not known and may further contribute to understanding differences in response rates. Approximately 85% of patients with ADPKD are reported to have a mutation in the PKD1 gene, while the remaining 15% have a mutation in the PKD2 gene. Measured levels of these biomarkers (PC1 and PC2) inversely correlate with disease severity and are believed to be directly linked to the underlying genetic drivers of the disease. Regulus believes these initial data demonstrate that RGLS4326 engages the target miR-17 leading to de-repression of the PKD1 and PKD2 genes and the resultant increases in measured polycystin levels. In addition to polycystin changes, one other notable improvement was observed in NGAL levels for one patient in the first cohort. As anticipated, NGAL levels for nearly all patients in this study were within the normal range. However, one patient had levels that were approximately twice the normal range at baseline and that individual saw NGAL levels drop to within the normal range by the end of study. Further analyses of the data are ongoing to better understand drivers of response and correlations with baseline characteristics and other parameters. Data from this first cohort is planned to be submitted for presentation at Kidney Week, the American Society of Nephrology annual meeting being held in November 2021. "We are very pleased with these data as it provides the safety and pharmacokinetic data needed to complete the modeled safety margins and engage FDA on the remaining partial clinical hold requirements. We believe it also demonstrates clinical proof of mechanism by showing target engagement through increases in a biomarker that inversely correlates with disease severity with a promising trend of increasing levels over time, suggesting that with extended dosing, further increases in polycystin may be attainable," said Jay Hagan, CEO of Regulus. "These results validate our efforts in targeting miR-17 in the kidney and give us confidence in our overall program, with our lead molecule, RGLS4326, now in the second cohort of this Phase 1b study and our next generation compound in IND preparation. We want to thank all of the patients, investigators and collaborators we continue to work with in advancing this novel program designed to address this significant disease at the genetic level." Conference Call & Webcast Information Regulus will host a conference call and webcast at 8:30 a.m. Eastern Time today to discuss the top-line results from the available data at the time of this analysis from the first cohort of patients in our ongoing Phase 1b study of RGLS4326 in patients with ADPKD. To access the call, please dial (877) 257-8599 (domestic) or (970) 315-0459 (international) and refer to conference ID 9988705. To access the telephone replay of the call, dial (855) 859-2056 (domestic) or (404) 537-3406 (international), passcode ID 9988705. The webcast and telephone replay will be archived on the company's website at for ninety days following the call. About RGLS4326 Phase 1b The Phase 1b is an adaptive design, open-label, multiple dose study in up to three cohorts of patients with ADPKD. The study is designed to evaluate the safety, pharmacokinetics, and changes in levels of polycystin 1 (PC1) and polycystin 2 (PC2) in patients with ADPKD administered RGLS4326 every other week for a total of four doses. The dose level for the first cohort is 1mg/kg of RGLS4326 and the dose level for the second cohort is 0.3mg/kg. The third and final cohort will be dosed at a level to be determined based on the results of the first two cohorts. For more information about the clinical trial design, please visit (NCT04536688). About RGLS4326 RGLS4326 is a novel oligonucleotide designed to inhibit miR-17 and designed to preferentially target the kidney. Preclinical studies with RGLS4326 have demonstrated direct regulation of Pkd1 and Pkd2, reduction of cyst growth in human in vitro ADPKD models, and attenuation of cyst proliferation and improvement of kidney function in mouse models of ADPKD. The RGLS4326 IND is currently on a Partial Clinical Hold for treatment of extended duration by FDA until the second set of requirements outlined by the agency have been satisfactorily addressed. The Company will use information from the Phase 1 clinical studies, including the first cohort of the Phase 1b study together with information from the recently completed additional nonclinical studies generated in 2020, in its plan to address the second set of requirements outlined in the Partial Clinical Hold letter to support studies of extended duration. Regulus plans to discuss its approach to addressing the remaining Partial Clinical Hold requirements with FDA in mid-2021. RGLS4326 has received orphan drug designation from FDA in July 2020. About ADPKD ADPKD, caused by the mutations in the PKD1 or PKD2 genes, is among the most common human monogenic disorders and a leading cause of end-stage renal disease. The disease is characterized by the development of multiple fluid filled cysts primarily in the kidneys, and to a lesser extent in the liver and other organs. Excessive kidney cyst cell proliferation, a central pathological feature, ultimately leads to end-stage renal disease in approximately 50% of ADPKD patients by age 60. About Regulus Regulus Therapeutics Inc. (Nasdaq: RGLS) is a biopharmaceutical company focused on the discovery and development of innovative medicines targeting microRNAs. Regulus has leveraged its oligonucleotide drug discovery and development expertise to develop a pipeline complemented by a rich intellectual property estate in the microRNA field. Regulus maintains its corporate headquarters in La Jolla, CA. 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, including statements associated with the clinical activities concerning the RGLS4326 program, including the preliminary biomarker, pharmacokinetic and safety data resulting from the first cohort of patients from the ongoing clinical study, the sufficiency of the data required to recommence clinical studies for extended duration dosing, the timing of the Company's interactions with FDA regarding the clinical hold and the timing and of other preclinical and clinical activities. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Regulus' current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and in the endeavor of building a business around such drugs, and feedback from the FDA. In addition, while Regulus expects the COVID-19 pandemic to adversely affect its business operations and financial results, the extent of the impact on Regulus' ability to achieve its preclinical and clinical development objectives and the value of and market for its common stock, will depend on future developments that are highly uncertain and cannot be predicted with confidence at this time, such as the ultimate duration of the pandemic, travel restrictions, quarantines, social distancing and business closure requirements in the U.S. and in other countries, and the effectiveness of actions taken globally to contain and treat the disease. These and other risks are described in additional detail in Regulus' filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. Regulus undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Company Codes: NASDAQ-NMS:RGLS