MICA: Targeting the RA synovial fibroblast via cyclin dependent kinase inhibition - a phase IIa study

MICA：通过细胞周期蛋白依赖性激酶抑制作用靶向 RA 滑膜成纤维细胞 - IIa 期研究

• 批准号: MR/L005123/1
• 负责人: John Isaacs
• 金额: $ 167.15万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL005123%2F1
• 关键词: MICA; Targeting; RA; synovial; fibroblast

Context Rheumatoid arthritis (RA) is a condition in which the joints become inflamed and painful. It affects about 1 in every 100 adults in the UK. It is thought to be caused by the patient's immune system mistakenly attacking their joints. The resulting inflammation is not only painful but reduces joint movement and eventually causes joint damage and deformity. RA can also affect other organs such as the lungs, and patients with RA also have a higher than average risk of developing heart attacks and strokes. They are also more susceptible to infections. Many patients lose their jobs soon after the diagnosis is made.Aims and objectivesMost drugs currently used to treat RA neutralise the inflammation (anti-inflammatory drugs, steroids) or the cells of the immune system and their products (biological therapies or 'magic bullets'). Over the past 20 years the outcome for RA patients has improved, partly because of earlier and more 'aggressive' treatment (more drugs, higher doses) and partly because of new therapies that have been developed (particularly the 'magic bullets'). However, many patients don't respond completely to these treatments and some don't respond at all. We believe that there is another type of cell responsible for the symptoms in these patients. The fibroblast is a cell that is present in healthy joints, where it is important for normal joint function. However, fibroblasts divide inappropriately and become more numerous and 'aggressive' in RA joints. They damage the joint by producing chemicals that eat into cartilage and bone, and also produce inflammatory chemicals themselves. Thus, a useful cell in health becomes one that causes inflammation and joint damage in RA. As far as we know none of the current treatments affect the behaviour of fibroblasts. Our plan is test a drug in RA patients that we think will do so. The drug interferes with the machinery that is necessary for cells to divide. Fibroblasts in the RA joint seem particularly sensitive to this drug, which we therefore believe can correct their abnormal behaviour. The drug has already been tested in patients with certain types of cancer (in which cells also divide inappropriately) and seems safe enough to test in RA. We aim to show that the treatment is safe in RA, and that it could provide a useful treatment for RA patients. The research is divided into two parts. In the first part we will test the safety of different doses of the drug over 4 weeks of treatment. We will identify a dose that is both safe and appropriate to test in more patients for a longer period of time. In the second part we will give this dose to 12 RA patients for 12 weeks. At the same time 6 patients will receive an identical 'placebo' treatment. This is important to ensure that any effects we see are due to the drug and not other factors (more visits to the hospital, more interaction with doctors and nurses). As well as checking the patients' symptoms, we will also perform scans of their joints at the start and end of the treatment. We will also take small samples of joint tissue (biopsies). These scans and biopsies will help us to decide whether the treatment is working and how it is working. This is important to help us to decide whether the trial has been a 'success' and whether to perform further trials later on. Potential applications and benefitIn this trial we will treat patients who have had RA for at least a year and who are already taking treatment but not responding well enough. This will test our idea that we can improve their symptoms by altering the behaviour of the fibroblasts. If this research is successful then we will need to test the treatment in RA patients taking different treatments, at different stages of their illness. Because this treatment works in such a different way to existing drugs, we believe it could be useful for many different types of RA patient. Later on, if safe and effective, it may also be useful in other diseases.

风湿性关节炎（RA）是一种关节发炎和疼痛的疾病。在英国，每100个成年人中就有1个受到影响。它被认为是由患者的免疫系统错误地攻击他们的关节引起的。由此产生的炎症不仅疼痛，而且会减少关节运动，最终导致关节损伤和畸形。RA也会影响其他器官，如肺部，RA患者患心脏病和中风的风险也高于平均水平。他们也更容易受到感染。目的和目标目前用于治疗RA的大多数药物都是中和炎症（抗炎药、类固醇）或免疫系统细胞及其产物（生物疗法或“神奇子弹”）。在过去的20年里，RA患者的结果有所改善，部分原因是早期和更“积极”的治疗（更多的药物，更高的剂量），部分原因是已经开发的新疗法（特别是“神奇子弹”）。然而，许多患者对这些治疗没有完全反应，有些根本没有反应。我们认为，有另一种类型的细胞负责这些患者的症状。成纤维细胞是一种存在于健康关节中的细胞，它对正常关节功能很重要。然而，成纤维细胞分裂不适当，并成为更多的RA关节和“侵略性”。它们通过产生腐蚀软骨和骨骼的化学物质来破坏关节，并且自身也产生炎症化学物质。因此，健康中有用的细胞变成了导致RA炎症和关节损伤的细胞。据我们所知，目前的治疗方法都不会影响成纤维细胞的行为。我们的计划是在类风湿性关节炎患者身上测试一种我们认为会这样做的药物。这种药物干扰细胞分裂所必需的机制。RA关节中的成纤维细胞似乎对这种药物特别敏感，因此我们相信这种药物可以纠正它们的异常行为。该药物已经在某些类型的癌症患者（其中细胞也不适当地分裂）中进行了测试，并且似乎足够安全，可以在RA中进行测试。我们的目的是证明这种治疗在RA中是安全的，并且它可以为RA患者提供有用的治疗。本研究分为两个部分。在第一部分中，我们将测试4周治疗期间不同剂量药物的安全性。我们将确定一个既安全又适合在更多患者中进行更长时间测试的剂量。在第二部分中，我们将给12名RA患者服用该剂量12周。同时，6名患者将接受相同的“安慰剂”治疗。这一点很重要，以确保我们看到的任何影响都是由于药物而不是其他因素（更多地去医院，更多地与医生和护士互动）。除了检查患者的症状外，我们还将在治疗开始和结束时对他们的关节进行扫描。我们还将采集关节组织的小样本（活检）。这些扫描和活检将帮助我们决定治疗是否有效以及如何起作用。这对我们决定试验是否成功以及以后是否进行进一步的试验是很重要的。潜在的应用和益处在这项试验中，我们将治疗患有RA至少一年的患者，以及已经接受治疗但反应不够好的患者。这将测试我们的想法，我们可以通过改变成纤维细胞的行为来改善他们的症状。如果这项研究是成功的，那么我们将需要测试在RA患者接受不同治疗，在他们的疾病的不同阶段的治疗。由于这种治疗方法与现有药物的作用方式如此不同，我们相信它对许多不同类型的RA患者都有用。以后，如果安全有效，它也可能对其他疾病有用。

项目成果

Impact of the COVID-19 pandemic on recruitment to clinical research studies in rheumatology.

• DOI: 10.1002/msc.1561
• 发表时间: 2022-03
• 期刊: Musculoskeletal care
• 影响因子: 1.3
• 作者: Mirza M;Siebert S;Pratt A;Insch E;McIntosh F;Paton J;Wright C;Buckley CD;Isaacs J;McInnes IB;Raza K;Falahee M
• 通讯作者: Falahee M

TRAFIC: statistical design and analysis plan for a pragmatic early phase 1/2 Bayesian adaptive dose escalation trial in rheumatoid arthritis.

TRAFIC：类风湿关节炎实用早期 1/2 期贝叶斯自适应剂量递增试验的统计设计和分析计划。

• DOI: 10.1186/s13063-021-05384-5
• 发表时间: 2021-07-06
• 期刊: Trials
• 影响因子: 2.5
• 作者: Cole M;Yap C;Buckley C;Ng WF;McInnes I;Filer A;Siebert S;Pratt A;Isaacs JD;Stocken DD
• 通讯作者: Stocken DD

Biologic refractory disease in rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.

• DOI: 10.1136/annrheumdis-2018-213378
• 发表时间: 2018-10
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4
• 作者: Kearsley-Fleet L;Davies R;De Cock D;Watson KD;Lunt M;Buch MH;Isaacs JD;Hyrich KL;BSRBR-RA Contributors Group
• 通讯作者: BSRBR-RA Contributors Group

AB0356 TARGETING THE RHEUMATOID ARTHRITIS SYNOVIAL FIBROBLAST VIA CYCLIN DEPENDENT KINASE INHIBITION (TRAFIC): A PHASE 1B STUDY TO DETERMINE THE MAXIMUM TOLERATED DOSE OF SELICICLIB FOR REPURPOSING IN RHEUMATOID ARTHRITIS

AB0356 通过细胞周期蛋白依赖性激酶抑制 (TRAFIC) 靶向类风湿性关节炎滑膜成纤维细胞：一项 1B 期研究，以确定 SELICICLIB 在类风湿性关节炎中的重新用途的最大耐受剂量

• DOI: 10.1136/annrheumdis-2020-eular.2443
• 发表时间: 2020
• 期刊: Annals of the Rheumatic Diseases
• 影响因子: 27.4
• 作者: Pratt A

Mesenchymal cells in health and disease.

健康和疾病中的间充质细胞。

• DOI: 10.1038/s41590-022-01318-8
• 发表时间: 2022
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Koliaraki V