From therapeutic mechanisms to unraveling the pathophysiology of MS

从治疗机制到揭示多发性硬化症的病理生理学

• 批准号: 10927913
• 负责人: Bibiana Bielekova
• 金额: $ 134.32万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927913
• 关键词: Acute; Age; Animal Experiments; Axon; Binding; Bioinformatics; Biological Markers; Biological Process; Blood - brain barrier anatomy; Blood Cells; Cardiovascular Diseases; Cell Death; Cells; Central Nervous System; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Data; Demyelinations; Development; Disabled Persons; Disease; Disease remission; Drops; Drug Combinations; Drug Targeting; Endothelium; Enhancing Lesion; Etiology; Exclusion; FDA approved; Fumarates; Functional disorder; Future; Heart; Human; Hydroxychloroquine; Hypertension; Immune; Individual; Inflammasome; Inflammation; Inflammatory; Injury; Knowledge; Lesion; Losartan; Magnetic Resonance Imaging; Measurable; Measurement; Measures; Meta-Analysis; Methodology; Modeling; Molecular; Multiple Sclerosis Lesions; Myelogenous; Nervous System Trauma; Neurologic; Oligodendroglia; Outcome; Pathogenicity; Pathology; Patient Selection; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase II Clinical Trials; Prevalence; Process; Proteomics; Protocols documentation; Purinoceptor; Relapse; Reporting; Reproducibility; Residual state; Safety; Sample Size; Severities; Severity of illness; Signal Pathway; Signal Transduction; Speed; System; Testing; Therapeutic; Therapeutic Agents; Thrombophilia; Tight Junctions; Time; Tissues; Toxic effect; Uncertainty; Validation; biomarker validation; blood-brain barrier crossing; disability; drug development; drug testing; effective therapy; exhaust; extracellular; glucose metabolism; immunoregulation; in silico; in vivo; individual patient; knowledge base; lipid disorder; lipid metabolism; montelukast; multiple sclerosis patient; multiple sclerosis treatment; novel; patient population; precision medicine; prospective; recruit; remyelinating agent; remyelination; repaired; screening; successful intervention; tool

At MS inception, relapsing-remitting MS (RRMS) patients form focal lesions, quantified as contrast-enhancing lesions (CELs) on MRI. CELs are associated with the influx of immune cells from peripheral blood and opening of blood brain barrier (BBB) endothelial tight junctions. This focal inflammation is destructive to resident central nervous system (CNS) cells, resulting in focal demyelination and axonal transection. This leads to acute development of neurological disability presenting as MS relapse. Every CEL/relapse leads to permanent damage because human CNS transected axons do not regenerate, even if we cannot always measure this as permanent disability. Current FDA-approved immunomodulatory disease-modifying treatments (DMTs) are highly effective in inhibiting CELs and MS relapses, which we call in this review MS lesional activity. However, CELs and MS relapses diminishes as patients age and are rare after the 5th decade, even in untreated subjects. The mechanisms of MS progression that are not associated with the formation of new MS lesions well call here non-lesional MS activity. While the most efficacious DMTs inhibit CELs by more than 90% and do so equally in patients of all ages, the efficacy of DMTs on disability progression is much lower and decreases linearly with advancing patient age. Indeed, the meta-analysis of MS clinical trials shows that when initiated after age of 53 years, DMTs do not have measurable effect on disability progression. Based on age-prevalence of MS, this means that over 40% of patients living with MS have no effective treatment options and another 40% have sub-optimal benefit from current FDA-approved treatments. Therefore there remains very strong societal need for developing new treatments for MS that target non-lesional MS activity. What mechanisms drive MS progression once MS lesions stop forming is not known, although candidate mechanisms were identified in MS pathology studies and more recently from CSF biomarker studies (see AI001242-05). Causality of any candidate pathogenic process can be validated only in a successful interventional clinical trial. Currently, even the most sensitive disability outcomes require prohibitively large sample sizes (1000 patients treated for 2-3 years) to demonstrate efficacy of a single drug on inhibiting MS disability progression. This effectively permits testing only 1 drug for progressive MS worldwide at any given time, yielding unacceptably slow therapeutic progress for this underserved patient population. This project and associated adaptive, platform Phase II clinical trial TRAP-MS: Targeting Residual Activity by Precision, biomarker-guided combination therapies of Multiple Sclerosis (clinicaltrials.gov identifier NCT03109288) explores different paradigm of drug development and target(s) validation in MS patients with measurable disability progression despite current FDA-approved treatments. In concordance with systemic polygenic diseases such as cardiovascular diseases (CVD), we hypothesize that CNS damage in longstanding (progressive) MS is molecularly complex and intra-individually heterogeneous. Additionally, it is likely that disability accumulates after most endogenous regulatory and repair mechanisms have been exhausted. This leads us to hypothesize that if progressive accumulation of disability can be successfully inhibited (this remains unknown), it will require comprehensive measurements of patient-specific pathogenic mechanism(s) and attempts to limit them simultanously by using rational drug combinations. CVD-contributing mechanisms, such as hypertension, disorders of lipid and glucose metabolism, hypercoagulable state, and injuries to systems components (i.e., heart and vessels) must be analyzed in individual patients and if found abnormal, must be treated simultaneously. Without such patient-specific targeting, any cardiovascular DMT administered as monotherapy to all CVD patients would have marginal efficacy that would be very difficult to prove during drug development. The same is true for any chronic polygenic disorder, including MS. Thus, TRAP-MS trial aims to study CSF biomarkers in patients with advanced (progressive) MS who accumulate measurable disability progression while on FDA-approved treatments and without forming new MS lesions. Thus, these patients are progressing by non-lesional MS activity. CSF biomarker measurements in these patients are used to enhance knowledge about candidate disease mechanisms and to simultanously measure intrathecal pharmacodynamic (IPD) effects of tested drugs on such candidate pathogenic processes. We initiated TRAP-MS trial in 2017 lacking ability to comprehensively measure candidate pathogenic mechanisms in living people, lacking knowledge which of these may correlate with MS severity (i.e., speed of disability accumulation) or what are the IPD effects of drugs proposed for testing. Acknowledging this uncertainty in scientific and regulatory approvals, this protocol effectively aimed at filling this essential knowledge gap. As TRAP-MS recruits people progressing despite current DMTs (mostly older, moderately to severely disabled subjects excluded from pharma-sponsored trials) it targets understudied patient population with the greatest therapeutic need. The rationale for testing specific drugs, defined in the protocol, is beyond the limits of this report. Based on protocol-defined criteria, we have dropped from further testing 3 initial drugs because their IPD effects were insufficient: montelukast (showed no discernable IPD), losartan (showed intrathecal inhibition of ACE, but no desirable effects on MS severity) and hydroxychloroquine (showed expected decrease in intrathecal inflammation measured by CSF sCD27, but the decrease was <10% and remaining IPD were unfavorable). We also stopped clemastine fumarate when 3/8 patients triggered safety stopping criteria. Clemastine was studied as remyelinating agent based on positive animal experiments and Phase II MS trial, to define IPD signature of remyelination. Instead, the CSF data showed that clemastine activated ATP binding and purinergic signaling pathways. This review period we significantly expanded mechanistic understanding of this toxicity by demonstrating that clemastine, as an allosteric modulator of P2RX7 purinergic receptor, sensitizes P2RX7 to open P2RX7-associated pore with lower extracellular ATP concentrations. This led to activation of innate immune cells of myeloid lineage, resulting in inflammasome in clemastine-treated patients. We showed that this prolonged P2RX7 signaling leads to pyroptotic, inflammatory cell death in primary human cells of myeloid lineage, but also in human oligodendrocytes. Furthermore, we identified pyroptosis signature from CSF proteomic biomarkers that is significantly increased in MS patients compared to healthy controls and that significantly correlates with MS severity (i.e., with the rates of accumulation of clinical disability). We showed that clemastine treatment significantly increases this pyroptosis signature in-vivo. These observations provide strong evidence that pyroptosis is one of the leading mechanisms of CNS tissue destruction in most (but not all) MS patients. The CSF-biomarker-based pyroptosis signature could be used as tool to pre-select patients and to confirm desired IPD effect of future treatments that target intrathecal pyroptosis. Longitudinal CSF biomarker data collected under TRAP-MS protocol allowed us to identify and validate biomarker-based models that reproducibly correlate with MS severity. We used this knowledge to apply bioinformatics approaches for in-silico prediction of drugs that might inhibit candidate pathogenic mechanisms if they can cross the blood brain barrier (which is usually unknown). The 4 drugs we already dropped from testing were not predicted to have d

在MS启动时，复发复发的MS（RRMS）患者形成局灶性病变，在MRI上定量为对比度增强病变（CELS）。 CELS与外周血和血液脑屏障（BBB）内皮紧密连接的开放有关。这种局灶性炎症对居民中枢神经系统（CNS）细胞具有破坏性，导致局灶性脱髓鞘和轴突横断。这导致神经残疾的急性发展为MS复发。每个CEL/复发都会导致永久损害，因为人类中枢神经系统的转移轴突不会再生，即使我们不能总是将其视为永久残疾。当前经FDA批准的免疫调节性疾病修饰治疗（DMTS）在抑制CELS和MS复发方面非常有效，我们在这次综述的MS行业活动中称之为这一点。然而，随着患者的年龄，CELS和MS会降低，并且在第5个十年之后，即使在未经治疗的受试者中也很少见。与新的MS病变的形成无关的MS进展机制很好地调用此处非静电MS活动。 尽管最有效的DMT抑制了CELS超过90％，并且在所有年龄段的患者中都同样这样做，但DMT对残疾进展的疗效却低得多，并且随着患者年龄的增长而线性降低。 实际上，MS临床试验的荟萃分析表明，在53岁以后启动时，DMT对残疾进展没有可测量的影响。基于MS的年龄偏差，这意味着超过40％的MS患者没有有效的治疗选择，而另外40％的患者可从当前FDA批准的治疗中获得优化的益处。因此，为针对非靶向MS活动的MS开发新的治疗方法仍然非常强大。 一旦MS病变停止形成，哪些机制驱动MS进展，尽管在MS病理研究中发现了候选机制，并且最近在CSF生物标志物研究中发现了候选机制（参见AI001242-05）。任何候选致病过程的因果关系只能在成功的介入临床试验中得到验证。目前，即使是最敏感的残疾结局，也需要大量的样本量（1000例接受治疗2 - 3年的患者），以证明一种药物在抑制MS残疾进展方面的功效。这有效地允许在任何给定时间在全球进行1种药物进行1种药物，从而为这个服务不足的患者人群带来不可接受的治疗进展缓慢。 该项目和相关的适应性，平台II期临床试验陷阱-MS：通过精确，生物标志物引导的多发性硬化症的组合疗法（临床Trialtrials.gov识别剂NCT03109288）靶向残留活性。与全身性多基因疾病（例如心血管疾病（CVD））一致，我们假设长期以来（渐进式）MS中的CNS损伤是分子复杂的，并且是个体内异质性的。此外，在大多数内源性调节机制和修复机制已经耗尽后，残疾可能会累积。这使我们假设，如果可以成功抑制残疾的逐渐积累（这仍然未知），则将需要对患者特异性病原机制进行全面的测量，并试图通过使用理性药物组合同时限制它们。在单个患者中，必须分析CVD - 归因机制，例如高血压，脂质和葡萄糖代谢疾病，高启动状态以及对系统组件的损伤（即心脏和血管），如果发现异常，则必须同时治疗。如果没有这种特定于患者的靶向，则任何对所有CVD患者进行单药治疗的心血管DMT都将具有边际疗效，这在药物开发过程中很难证明。对于包括MS在内的任何慢性多基因疾病，也是如此。 因此，TRAP-MS试验旨在研究高级（进行性）MS患者的CSF生物标志物，他们在FDA批准的治疗方法上积累了可测量的残疾进展，并且没有形成新的MS病变。因此，这些患者通过非静脉MS活性而进展。这些患者中的CSF生物标志物测量值用于增强有关候选疾病机制的知识，并同时测量测试药物对此类候选病原过程的鞘内药效学（IPD）作用。 我们在2017年启动了陷阱-MS试验，缺乏能够全面衡量活着的人的致病机制的能力，缺乏知识，其中可能与MS严重程度（即残疾速度积累速度）或提出测试的药物的IPD效应是什么是什么。该协议认识到科学和监管批准的这种不确定性，旨在填补这一基本知识差距。尽管陷阱-MS招募了当前的DMT（大多数年龄较大的，适度地被排除在制药赞助试验中的严重残疾受试者），但它以最大的治疗需求对患者人群进行了研究。 协议中定义的特定药物的测试基本原理超出了本报告的限制。根据协议定义的标准，我们已经从进一步测试3种初始药物中删除，因为它们的IPD效果不足：Montelukast（没有显示可识别的IPD），Losartan，Losartan（表现出对ACE的毛内抑制作用，对MS严重性没有可取的效果），并且预期的脑含量降低了Intratherecal rations intath intath intath rathem intath rathemation conffffffffffffffffffffffffffem的含量降低了。剩下的IPD是不利的）。当3/8例患者触发安全停止标准时，我们还停止了富马酸血清酸酯。根据阳性动物实验和II期MS试验，将Clemastine研究为透明剂，以定义Remereelination的IPD签名。取而代之的是，CSF数据表明，血丝素激活了ATP结合和嘌呤能信号传导途径。在本次审查期间，我们通过证明Clemastine作为P2RX7嘌呤能受体的变构调节剂来显着扩展对这种毒性的理解，使P2RX7敏感到开放P2RX7相关的孔具有较低的细胞外细胞ATP浓度。这导致了髓样谱系的先天免疫细胞的激活，从而导致炎症性治疗的患者炎症。我们表明，这种延长的P2RX7信号传导导致髓样谱系原代人细胞的凋亡，炎症细胞死亡，也导致人类的少突胶质细胞。 此外，我们确定了CSF蛋白质组学生物标志物的热吞作用，与健康对照组相比，MS患者的凋亡特征显着增加，并且与MS严重程度显着相关（即与临床残疾的积累率）。我们表明，血红素治疗显着增加了该体内的凋亡特征。这些观察结果提供了有力的证据，表明大多数（但不是全部）MS患者中CNS组织破坏的主要机制之一。基于CSF的基于CSF-BIOMARKER的凋亡特征可以用作预选患者的工具，并确认靶向鞘内毒性凋亡的未来治疗的所需IPD效应。 纵向CSF生物标志物数据在陷阱-MS协议下收集的数据使我们能够识别并验证基于生物标志物的模型，这些模型与MS严重性相关。我们使用这些知识来应用生物信息学方法，以预测药物，如果它们可以越过血液脑屏障（通常是未知），这些药物可能会抑制候选的致病机制。我们已经从测试中掉下的4种药物没有预测

项目成果

Machine learning-optimized Combinatorial MRI scale (COMRISv2) correlates highly with cognitive and physical disability scales in Multiple Sclerosis patients.

• DOI: 10.3389/fradi.2022.1026442
• 发表时间: 2022
• 期刊: Frontiers in radiology
• 作者: Kelly, Erin;Varosanec, Mihael;Kosa, Peter;Prchkovska, Vesna;Moreno-Dominguez, David;Bielekova, Bibiana
• 通讯作者: Bielekova, Bibiana

Aging and efficacy of disease-modifying therapies in multiple sclerosis: a meta-analysis of clinical trials.

• DOI: 10.1177/1756286420969016
• 发表时间: 2020
• 期刊: Therapeutic advances in neurological disorders
• 影响因子: 5.9
• 作者: Zhang Y;Gonzalez Caldito N;Shirani A;Salter A;Cutter G;Culpepper W 2nd;Wallin M;Kosa P;Bielekova B;Lublin F;Stuve O
• 通讯作者: Stuve O

Idebenone does not inhibit disability progression in primary progressive MS.

• DOI: 10.1016/j.msard.2020.102434
• 发表时间: 2020-10
• 期刊: MULTIPLE SCLEROSIS AND RELATED DISORDERS
• 影响因子: 4
• 作者: Kosa, Peter;Wu, Tianxia;Phillips, Jonathan;Leinonen, Mika;Masvekar, Ruturaj;Komori, Mika;Wichman, Alison;Sandford, Mary;Bielekova, Bibiana
• 通讯作者: Bielekova, Bibiana