The goal of the proposed project is to determine the safety and tolerability as well as the preliminary efficacy of a novel small molecule drug, S48168 (ARM210), for the treatment of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT1). This disease is associated with fatal changes in heart rhythms leading to sudden death with exercise or excessive excitement. It is due to mutations in the Ryanodine Receptor calcium release channel, which cause leaky channels leading to the disease. S48168 (ARM210) repairs these leaky channels and can be a disease-modifying therapy restoring normal function to the channels. This result would allow patients with CPVT to live normal, active lives. Funding Source- FDA OOPD.

开始日期2023-08-01

申办/合作机构

ARMGO Pharma, Inc.

NCT04141670 / Completed临床1期

Safety and Tolerability of S 48168 (ARM 210) for the Treatment of RYR1-related Myopathies (RYR1-RM)

This study proposes to test S 48168 (ARM210) in a Phase 1 trial in RYR1-RM patients, specifically. The objectives of this study are to explore the safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD)/target engagement (TE) of S 48168 (ARM210), as well as effects on muscle/motor function, and fatigue in RYR1-RM patients. The study population will include adult patients (≥18 years of age) who have demonstrated leaky RyR1 channels that are responsive to S48168 (ARM210) ex vivo.

开始日期2020-08-25

申办/合作机构

ARMGO Pharma, Inc.

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100 项与 Surlorian 相关的专利（医药）

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项与 Surlorian 相关的文献（医药）

2023-12-14·Journal of medicinal chemistry1区 · 医学

1,4-Benzothiazepines with Cyclopropanol Groups and Their Structural Analogues Exhibit Both RyR2-Stabilizing and SERCA2a-Stimulating Activities

1区 · 医学

Article

作者: Wegener, Jörg W ; Kiszka, Kamila A ; Mitronova, Gyuzel Y ; Belov, Vladimir N ; Lehnart, Stephan E ; Quentin, Christine

To discover new multifunctional agents for the treatment of cardiovascular diseases, we designed and synthesized a series of compounds with a cyclopropyl alcohol moiety and evaluated them in biochemical assays. Biological screening identified derivatives with dual activity: preventing Ca²⁺ leak through ryanodine receptor 2 (RyR2) and enhancing cardiac sarco-endoplasmic reticulum (SR) Ca²⁺ load by activation of Ca²⁺-dependent ATPase 2a (SERCA2a). The compounds that stabilize RyR2 at micro- and nanomolar concentrations are either structurally related to RyR-stabilizing drugs or Rycals or have structures similar to them. The novel compounds also demonstrate a good ability to increase ATP hydrolysis mediated by SERCA2a activity in cardiac microsomes, e.g., the half-maximal effective concentration (EC₅₀) was as low as 383 nM for compound 12a, which is 1,4-benzothiazepine with two cyclopropanol groups. Our findings indicate that these derivatives can be considered as new lead compounds to improve cardiac function in heart failure.

2022-07-22·Science advances

Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment

Article

作者: Marks, Andrew R. ; Dridi, Haikel ; Liu, Yang ; Wronska, Anetta ; Melville, Zephan ; Weninger, Gunnar ; Miotto, Marco C. ; Reiken, Steven ; Yuan, Qi ; Sittenfeld, Leah

Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca 2+ leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo–electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a “primed” state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca 2+ leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210.

2022-07-01·Structure (London, England : 1993)

It takes two to tango: Rycals and ATP snuggle up to bind ryanodine receptors

Article

作者: Pancaroglu, Raika ; Van Petegem, Filip

In this issue of Structure, Melville and colleagues used cryo-EM to study the binding of ryanodine receptors to Rycals, compounds with the potential to treat skeletal and cardiac muscle disorders. Unexpectedly, they found that Rycal packs against an ATP in a peripheral pocket, which stabilizes the closed channel state.

项与 Surlorian 相关的新闻（医药）

2024-02-05

·药明康德

初治患者完全缓解率达100%的联合疗法；使月度发作率下降95%的基因编辑疗法... | 一周盘点

▎药明康德内容团队编辑本期看点1. “明星”小分子ziftomenib联合标准治疗的早期数据亮眼，特定初治急性髓系白血病（AML）患者100%获得了完全缓解（CR）。2. 用于治疗遗传性血管水肿（HAE）的在研体内CRISPR基因编辑疗法NTLA-2002早期临床数据亮眼，单次给药后使所有患者的月度发作率平均下降了95%。3. 首个获美国FDA许可进入临床试验的RNA外显子编辑疗法ACDN-01被授予快速通道资格。药明康德内容团队整理Ziftomenib：公布1期临床试验数据Kura Oncology公司公布了ziftomenib联合标准治疗，包括阿糖胞苷/达柔比星（7+3）和维奈托克/阿扎胞苷（ven/aza），治疗NPM1突变型（NPM1-m）和KMT2A重排型（KMT2A-r）急性髓系白血病患者的1期临床试验的初步数据。Ziftomenib是一种针对menin与KMT2A/MLL蛋白复合体之间相互作用的在研候选药物，用于治疗有高度未满足需求，携带特定基因突变的AML患者。在临床前模型中，ziftomenib抑制了KMT2A/MLL蛋白复合体，并表现出强大的抗白血病活性。Ziftomenib已获得FDA授予的孤儿药资格，用于治疗AML。这款在研新药曾被猎药人网站（drughunter.com）列为2022年度10大“明星”小分子之一。截至2024年1月11日的数据，在新诊断的NPM1-m型和KMT2A-r型AML患者中，接受ziftomenib联合7+3治疗的CR率为100%；未接受过menin抑制剂治疗的难治/复发（R/R）性AML患者接受ziftomenib联合ven/aza治疗，CR/完全缓解伴部分血液学恢复（CRh）率为56%。安全性方面，连续每天服用200 mg ziftomenib的耐受性良好，其安全性与基础疾病和主要治疗方法的特征一致。NTLA-2002：公布1期临床试验的中期数据Intellia Therapeutics公司在《新英格兰医学杂志》（NEJM）上公布了其在研体内CRISPR基因编辑疗法NTLA-2002的1/2期临床试验的中期分析结果。NTLA-2002旨在使用CRISPR/Cas9技术对激肽释放酶B1（KLKB1）基因进行编辑，该基因负责编码激肽释放酶前体蛋白。通过让KLKB1失活，NTLA-2002可永久性降低激肽释放酶活性，以达到治愈HAE的目的。NTLA-2002包含靶向致病基因的指导RNA（gRNA），和编码Cas9酶的mRNA，它们共同开展精准编辑。结果显示，在最近一次随访中，单次给药NTLA-2002使所有患者（n=10）的HAE月度发作率平均下降了95%；在16周的主要观察期后，所有血浆激肽（kallikrein）水平降低超过60%以上的患者（n=9）仍然完全没有发作，最长的无发作间隔期已达13.0个月，并且还在持续；在所有在使用NTLA-2002后停止长期HAE预防治疗的患者（n=6）中，自停止治疗后还没有报告过HAE发作。此外，NTLA-2002在所有剂量水平上都有良好的耐受性。报告的最常见的不良事件是轻度、短暂的输液相关反应和疲劳。ACDN-01：IND申请获得FDA许可Ascidian Therapeutics公司宣布其在研RNA外显子编辑疗法ACDN-01的IND申请已经获得美国FDA的许可，并被授予快速通道资格。ACDN-01是一种在体内编辑RNA外显子的RNA编辑疗法。它通过单一载体递送，已在非人类灵长类动物的体内实验以及人类视网膜的体外实验中显示出有效且持久的RNA外显子编辑。与其它只修改一个RNA碱基的RNA编辑器不同，ACDN-01的独特之处在于能够重新书写RNA序列，将导致疾病的RNA序列替换为功能正常的RNA序列，具有使用一种疗法，治疗多种基因突变导致的Stargardt病的潜力。此外，RNA编辑疗法与基于CRISPR的基因组编辑疗法相比，由于不会对基因组序列产生永久影响，可能具有更高的安全性。新闻稿指出，ACDN-01是首个获美国FDA许可进入临床试验的RNA外显子编辑疗法，并且是首款专门针对Stargardt病遗传起源的临床期治疗方法。Ascidian预计在2024年上半年开始招募参与ACDN-01针对Stargardt病及其他ABCA4相关视网膜病变的1/2期临床试验STELLAR的患者。JAG201：IND申请获得FDA许可Jaguar Gene Therapy公司宣布，美国FDA已经批准了其用于治疗遗传性自闭症谱系障碍（ASD）和Phelan-McDermid综合征（PMS）的基因疗法JAG201的IND申请。JAG201旨在通过AAV9载体提供SHANK3基因的功能拷贝，持久地恢复学习和记忆所需的突触功能，从而从根本上治疗ASD和PMS。啮齿动物和非人灵长类动物的临床前研究表明，递送功能性SHANK3可改善神经行为、认知和运动功能异常。该公司计划于2024年下半年在美国启动一项1期试验，针对SHANK3突变或缺失的ASD或PMS成人患者。Deltacel：公布1期临床试验中首例患者的数据Kiromic BioPharma公司公布了其在研γ-δ T细胞（GDT）疗法Deltacel用于治疗转移性非小细胞肺癌（NSCLC）的1期临床试验的积极初步数据，该疗法在首例患者中展现出良好的早期疗效结果。Deltacel是一种同种异体细胞治疗产品，由未经修饰的供体来源GDT组成。Deltacel旨在利用GDT的天然效力靶向实体瘤，最初的临床开发重点是NSCLC（约占肺癌病例的80%至85%）。两项临床前研究的数据表明，Deltacel与低剂量放射治疗相结合具有良好的安全性和有效性。积极的初步证据证明了Deltacel在控制NSCLC生长方面的疗效。Deltacel的耐受性仍然良好，进一步证实早期安全性评估结果。首例患者在比佛利山癌症中心（BHCC）接受了治疗，并在开始治疗前三天被确诊为病情进展活跃的患者。接受Deltacel治疗六周后，CT扫描证实了此患者的病情稳定，初步的无进展生存期为一个半月。Risvodetinib：公布1期临床试验数据Inhibikase Therapeutics公司公布了其c-Abl抑制剂risvodetinib治疗老年帕金森病（PD）患者的1期临床试验的数据。结果显示，risvodetinib单次或多次给药在所有受试者中表现出良好的安全性和耐受性。健康受试者中未出现严重不良事件，服用抗PD药物的PD患者也未出现症状恶化。该公司正继续积极招募患者参加其2期试验，以评估risvodetinib对未经治疗的帕金森病患者的治疗效果。ARM210（S48168）：公布1b期临床试验数据ARMGO Pharma公司公布了其靶向ryanodine受体钙释放通道（RyR）的小分子药物ARM210（又称S48168）的1b期研究结果，该药拟用于治疗一种罕见的肌肉疾病——ryanodine受体1型相关肌病（RYR1-RM）。该1b期研究证实了每天服用120 mg和200 mg ARM210在RYR1-RM患者中的安全性和耐受性，并首次在临床上展现了每日服用200 mg ARM210可改善患者疲劳和近端肌力的迹象。此外，该研究还证实了ARM210能够通过修复由突变的RyR1通道造成的细胞内钙泄漏以恢复肌肉功能的作用机制。EC5026：启动1b期临床试验EicOsis Human Health宣布启动一项1b期多剂量递增试验，以评估其小分子候选药物EC5026的安全性。EC5026是一种强效、高选择性的可溶性环氧化物水解酶（sEH）抑制剂，在调节信号脂质的代谢、响应由创伤或疾病引起的炎症和其他应激反应方面发挥着至关重要的作用。通过抑制sEH，EC5026能阻止天然镇痛和抗炎脂肪酸的分解，从而缓解疼痛，是一种治疗中度至重度疼痛的潜在非阿片类药物。临床前研究表明，EC5026不会产生镇静或其他不良行为，也没有成瘾迹象。VTR-297：IND申请获得FDA许可Vanda Pharmaceuticals公司宣布，美国FDA已经批准了其小分子组蛋白脱乙酰酶（HDAC）抑制剂VTR-297用于治疗甲癣的IND申请。VTR-297具有抗皮癣菌和真菌的活性，最开始是作为一种抗真菌抗生素从酵母菌种Streptomyces hygroscopicus中被分离出来，于1976年首次被描述。自2014年以来，美国FDA尚未批准任何新的甲癣治疗方法。启动VTR-297治疗甲癣的临床研究是研究和开发治疗这种常见疾病的潜在新疗法的一个重要里程碑。大家都在看药明康德为全球生物医药行业提供一体化、端到端的新药研发和生产服务，服务范围涵盖化学药研发和生产、生物学研究、临床前测试和临床试验研发、细胞及基因疗法研发、测试和生产等领域。如您有相关业务需求，欢迎点击下方图片填写具体信息。▲如您有任何业务需求，请长按扫描上方二维码，或点击文末“阅读原文/Read more”，即可访问业务对接平台，填写业务需求信息▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看）[1] Ascidian Therapeutics Announces First-Ever IND for an RNA Exon Editor as FDA Approves Trial Plan and Fast Tracks ACDN-01 in Stargardt Disease and Other ABCA4 Retinopathies. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/ascidian-therapeutics-announces-first-ever-ind-for-an-rna-exon-editor-as-fda-approves-trial-plan-and-fast-tracks-acdn-01-in-stargardt-disease-and-other-abca4-retinopathies-302046287.html[2] ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies. Retrieved January 30, 2024, from https://www.globenewswire.com/news-release/2024/01/29/2818472/0/en/ARMGO-Pharma-Publishes-Positive-Phase-1b-Trial-Results-of-Rycal-ARM210-for-the-Treatment-of-Ryanodine-Receptor-1-Related-Myopathies.html[3] Inhibikase Therapeutics Announces Publication Highlighting Results from its Phase 1 Studies with Risvodetinib. 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Retrieved January 30, 2024, from https://ir.lixte.com/news-events/press-releases/detail/101/first-patient-dosed-with-lixtes-lb-100-and-gsks-immunotherapy-dostarlimab-gxly-in-ovarian-clear-cell-carcinoma-trial[8] Uvax Bio Announces Dosing of First Participant in Phase 1 Clinical Trial Evaluating Two Vaccines to Prevent HIV-1 Infection. Retrieved January 30, 2024, from https://www.businesswire.com/news/home/20240129742089/en[9] EicOsis Initiates Phase 1b Clinical Trial of EC5026. Retrieved January 30, 2024, from https://www.prnewswire.com/news-releases/eicosis-initiates-phase-1b-clinical-trial-of-ec5026-302047230.html[10] KURA ONCOLOGY REPORTS POSITIVE PRELIMINARY ZIFTOMENIB COMBINATION DATA IN ACUTE MYELOID LEUKEMIA. Retrieved January 31, 2024, from https://ir.kuraoncology.com/news-releases/news-release-details/kura-oncology-reports-positive-preliminary-ziftomenib[11] Intellia Therapeutics Announces Publication of Positive Interim Phase 1 Data for NTLA-2002 in Patients with Hereditary Angioedema in the New England Journal of Medicine. Retrieved January 31, 2024, from https://www.globenewswire.com/news-release/2024/01/31/2821597/0/en/Intellia-Therapeutics-Announces-Publication-of-Positive-Interim-Phase-1-Data-for-NTLA-2002-in-Patients-with-Hereditary-Angioedema-in-the-New-England-Journal-of-Medicine.html[12] 23andMe Announces FDA Clearance of IND Application for its Dual Mechanism Antibody, 23ME-01473, Targeting ULBP6. 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Retrieved January 31, 2024, from https://www.prnewswire.com/news-releases/neurobo-pharmaceuticals-announces-fda-clearance-of-ind-for-a-phase-1-clinical-trial-of-da-1726-for-the-treatment-of-obesity-302050383.html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。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

基因疗法临床结果临床1期孤儿药快速通道

2024-01-29

·GlobeNewswire-Health Care

ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies

ARMGO Pharma Publishes Positive Phase 1b Trial Results of Rycal® ARM210 for the Treatment of Ryanodine Receptor 1 Related Myopathies Phase 1b open label trial confirms safety and tolerability of 120 mg and 200 mg dosing of ARM210 daily in patients with Ryanodine Receptor 1 Related Myopathies Provides first signs of clinical efficacy improving fatigue and proximal muscle strength in patients at 200 mg daily Corroborates allosteric mechanism of action of Rycal® ARM210 to restore muscle function by repairing mutated ‘leaky’ Ryanodine Receptor 1 channels January 29, 2024 – ARMGO Pharma, Inc. (ARMGO), a clinical stage biopharmaceutical company advancing a novel class of small molecule drugs known as Rycals®, announced today the publication of the results from a Phase 1b study of its Rycal ARM210 (also known as S48168), for the treatment of Ryanodine Receptor 1 Related Myopathies (RYR1-RM), an orphan muscle disease. The data was published in a paper entitled ‘Rycal S48168 (ARM210) for RYR1-related myopathies: A phase one, open-label, dose-escalation trial’ authored by Dr Joshua Todd et al in the peer reviewed Journal eClinicalMedicine, part of the Lancet family of publications. The paper reviews data from the Phase 1b study of ARM210 and its novel allosteric mechanism of action (MoA) targeting the root cause of RYR1-RM: mutated Ryanodine Receptor 1 (RYR1). The RYR1 gene encodes RyR1, an intracellular calcium-release channel that becomes leaky in muscle diseases. Intracellular calcium leaks caused by mutant RyR1 channels impair muscle contraction leading to muscle weakness and loss of function, and activate toxic pathways that damage muscle, causing the symptoms in RYR1-RM. The Phase 1b, open-label, dose-escalation trial confirmed safety, tolerability and pharmacokinetics of 120 and 200 mg dosing of ARM210 daily over for 29 days in adult men and women affected with RYR1-RM. Importantly, it also demonstrated preliminary efficacy in the higher dose group in two hallmark symptoms of RYR1-RM: 1) significant alleviation of fatigue assessed by PROMIS-fatigue t-scores and 2) improved proximal muscle strength assessed by physical shoulder abduction exam (Medical Research Council grading). These results warrant further development of ARM210 as a potential disease modifying treatment for RYR1-RM in a randomized, placebo-controlled Phase 2 trial. The completed Phase 1b trial was conducted in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) under a Cooperative Research and Development Agreement (CRADA), with the support of the RYR-1 Foundation, Pittsburgh, PA, USA. “We are very pleased with the results of the RYR1-RM trial conducted together with the NIH, as the study has confirmed the safety and tolerability of ARM210, but most importantly, it has demonstrated for the first time that our Rycal®, ARM210, can reverse symptoms of this devastating, chronic muscle disease in a short treatment period. That is very promising”, said Gene Marcantonio, M.D., Ph.D., Chief Executive Officer of ARMGO Pharma. “We look forward, therefore, to rapidly continuing the development of ARM210 to bring this potential first treatment to RYR1-RM patients with the support of the RYR-1 Foundation and the patient community.” Michael F. Goldberg, M.D., M.P.H., Co-Chair of Research of the RYR-1 Foundation added, “We are elated by the publication of this important study, as it represents a beacon of hope for the many individuals and families from around the world who are affected by RYR1-RM. We look forward to the next stages in the development of this important drug.” Further information about this Phase 1b trial can be found online at: https://clinicaltrials.gov/study/NCT04141670. The trial was supported by Intramural Research Programs of the NIH/NINDS, NIH/NINR, a NIH Clinical Center Bench to Bedside Award (2017-551673) and ARMGO’s previous collaboration partner Les Laboratoires Servier. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publication reference: Rycal S48168 (ARM210) for RYR1-related myopathies: a phase one, open-label, dose-escalation trial, Todd et al, eClinicalMedicine https://www-thelancet-com.libproxy1.nus.edu.sg/journals/eclinm/article/PIIS2589-5370(24)00012-9/fulltext ARM210 (S48168) is a small molecule of the Rycal class, owned and developed by ARMGO for the treatment of Ryanodine Receptor mediated diseases such as RYR1-RM. It is an allosteric modulator that binds preferentially to leaky RyR channels and repairs the leak, as previously demonstrated in vitro in muscle biopsies from RYR1-RM patients. ARM210 (S48168) is currently undergoing Phase 2 clinical development for a second orphan indication, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a genetic arrhythmia caused by mutations in RYR2, the cardiac calcium channel gene. ARM210 (S48168) was awarded orphan drug designation for RYR1-RM in 2018 by the FDA and for CPVT in 2020. ARMGO also has a rare pediatric disease designation for CPVT. ARMGO Pharma, Inc., is a privately held biopharmaceutical company dedicated to developing novel small-molecule therapeutics to treat cardiac, and musculoskeletal disorders characterized by leaky Ryanodine Receptor (RyR) calcium channels. The Company’s proprietary drugs, known as Rycals®, are a new class of oral agents that repair these leaky calcium channels. ARM210, ARMGO’s most advanced Rycal, is currently in clinical development for two rare and orphan diseases, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a life-threatening cardiac disease and RYR1-Related Myopathy (RYR1-RM) a severe muscle disease. ARMGO Pharma has an exclusive, worldwide license from Columbia University for its RyR technology based on the research of founding scientist Andrew R. Marks, M.D. The Pittsburgh, Pennsylvania-based 501(c)(3) public charity was launched in October 2014. It is currently the only organization that exists solely to advocate for and serve the needs of individuals affected by RYR-1-related diseases (RYR-1-RD), the most common cause of congenital myopathy. The RYR-1 Foundation supports research leading to an effective treatment or a cure for RYR-1-RD. To achieve this mission, The RYR-1 Foundation has several goals: 1) Support Research: The RYR-1 Foundation makes grants to researchers interested in RYR-1-RD. Developing a patient registry is also key to promoting clinical trials of potential therapies. 2) Medical Professional Education: The vast majority of medical professionals have never heard of RYR-1-RD. The RYR-1 Foundation raises awareness through resources on our website, including the latest medical literature, as well as direct meetings with medical professionals around the world. 3) Patient/Family Support and Advocacy: Due to the rarity of RYR-1-RD, receiving this diagnosis can be an anxiety-provoking and isolating experience for an affected patient and their families. The RYR-1 Foundation serves as a resource for patients and their families through our website, other forms of social media, and family conferences. The content above comes from the network. if any infringement, please contact us to modify.

临床结果孤儿药引进/卖出

2023-07-21

·生物谷

Nat Neurosci：揭示心力衰竭诱发机体认知功能下降的分子机制

来自哥伦比亚大学等机构的科学家们通过研究发现，心力衰竭或会通过在大脑神经元中产生微小的钙质泄露，从而导致机体认知功能下降，这一研究发现或有望帮助治疗心源性痴呆症。心力衰竭（HF，heart failure）患者的认知功能异常（CD，Cognitive dysfunction）常常会负面影响其对疗法的依从性和生活质量，尽管利阿诺定受体2型（RyR2，ryanodine receptor type 2)与心肌功能障碍有关，但其在HF患者中的认知功能异常中的作用，目前研究人员尚不清楚。近日，一篇发表在国际杂志Nature Neuroscience上题为“Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2”的研究报告中，来自哥伦比亚大学等机构的科学家们通过研究发现，心力衰竭或会通过在大脑神经元中产生微小的钙质泄露，从而导致机体认知功能下降，这一研究发现或有望帮助开发治疗心源性痴呆症（cardiogenic dementia）的新型疗法。医学博士Andrew R. Marks说道，多年以来，我们一直知道，心力衰竭患者往往会表现出认知功能损伤，但这往往被认为是一种巧合，直到最近研究人员发现，心力衰竭会导致机体出现认知问题，于是研究人员就假设，导致心力衰竭发生的细胞钙质渗漏或许会导致心力衰竭患者发生认知功能下降。在心脏细胞内，钙质会通过专用的通道流动，但在心力衰竭发生的早期阶段，当该通道被过度刺激时，其或许就无法被正常关闭，因此钙质就会通过该通道泄露，从而剥夺心脏细胞进行收缩时所需要的钙质，同时还会进一步促使心脏组织退化。揭示心力衰竭诱发机体认知功能下降的分子机制。图片来源：Nature Neuroscience (2023). DOI:10.1038/s41593-023-01377-6 因为研究人员在大脑中发现了相同的钙离子通道，于是研究人员决定去观察是否大脑细胞内钙质的泄露会引发机体的认知损伤问题。他们发现，在心力衰竭的小鼠中，大脑神经元中的钙质泄露会导致机体的认知损伤，但令人鼓舞的是，如果利用一种实验性的药物来堵塞钙质的泄露，机体的认知功能或许就能被得到保护。因心力衰竭而死亡的患者大脑中常常含有泄露的钙质通道，这或许就表明，这种泄露或许会引起人群机体发生认知损伤。研究人员针对这些泄露如何引发机体的认知问题提出了两种假设，第一种是逃逸的钙质或许会激活特定的酶类从而引发阿尔兹海默病患者机体中所观察到的反应，另外一种可能就是，这种泄露会导致大脑中传输信号所需的部分神经元出现异常。不管怎样，研究人员开发的实验性药物或能堵塞这种泄露并减缓心力衰竭的进展，从而有益于大脑的健康；而这种名为Rycals的药物目前也正在临床试验中，并用于治疗由钙离子通道泄露所引起的心脏和其它肌肉疾病。综上，本文研究结果中，研究人员提提出了心力衰竭或许是一种由细胞内钙离子泄露所驱动的系统性疾病，包括心源性痴呆症等。（生物谷Bioon.com）原始出处： Dridi, H., Liu, Y., Reiken, S. et al. Heart failure-induced cognitive dysfunction is mediated by intracellular Ca2+ leak through ryanodine receptor type 2. Nat Neurosci (2023). doi：10.1038/s41593-023-01377-6

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适应症	最高研发状态	国家/地区	公司	日期
室性心律失常	临床2期	美国	ARMGO Pharma, Inc.	2023-08-01
室性心律失常	临床2期	荷兰	ARMGO Pharma, Inc.	2023-08-01
儿茶酚胺敏感性多形性室性心动过速	临床2期	美国	ARMGO Pharma, Inc.	2023-07-19
儿茶酚胺敏感性多形性室性心动过速	临床2期	荷兰	ARMGO Pharma, Inc.	2023-07-19
Ryanodine Receptor Type 1 Related Myopathies	临床1期	美国	National Institute of Neurological Disorders & Stroke	2020-08-25
Ryanodine Receptor Type 1 Related Myopathies	临床1期	美国	ARMGO Pharma, Inc.	2020-08-25
肌营养不良	临床1期	欧洲	Les Laboratoires Servier SAS	2015-12-09
肢带型肌营养不良	临床1期	欧洲	ARMGO Pharma, Inc.	-
杜氏肌营养不良症	临床1期	欧洲	-	-
杜氏肌营养不良症	临床1期	-	ARMGO Pharma, Inc.	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04141670 (CTgov)	临床1期	Ryanodine Receptor Type 1 Related Myopathies	7	S48168 (Low Dose Group)	獵獵襯遞鹹範衊觸衊鹹(獵網顧網壓網積鏇築築) = 廠艱膚選製襯壓積網膚願醖醖夢衊簾夢構築顧 (願簾鹽膚鏇鹹網顧顧齋, 廠觸衊憲觸窪範積鏇淵 ~ 齋膚遞簾餘積衊壓餘鏇) 更多	-	2024-04-19
NCT04141670 (CTgov)	临床1期	Ryanodine Receptor Type 1 Related Myopathies	7	S48168 (High Dose Group)	獵獵襯遞鹹範衊觸衊鹹(獵網顧網壓網積鏇築築) = 齋網淵鏇願壓鑰築夢構願醖醖夢衊簾夢構築顧 (願簾鹽膚鏇鹹網顧顧齋, 網製餘壓構糧顧選網鹹 ~ 製鏇憲淵築簾窪構願憲) 更多	-	2024-04-19
NCT04141670 (GlobeNewswire) 人工标引	临床1期	Ryanodine Receptor Type 1 Related Myopathies	7	Rycal	製襯衊鑰鹹夢蓋製壓艱(顧襯築憲鏇製襯積鏇獵) = S48168 (ARM210) was well-tolerated, did not cause any serious adverse events, and exhibited a dose-dependent PK profile. 範積蓋築醖鏇窪遞衊鹽 (積窪糧艱積壓鑰鬱獵觸 ) 更多	积极	2024-01-29