MICA: Effect of CRTH2 Antagonist OC459 on Response to Rhinovirus Challenge in Asthma

MICA：CRTH2 拮抗剂 OC459 对哮喘鼻病毒攻击反应的影响

• 批准号: MR/M025330/1
• 负责人: Sebastian Johnston
• 金额: $ 173.97万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM025330%2F1
• 关键词: MICA; Effect; CRTH2; Antagonist; OC459

Asthma attacks are responsible for over 1000 deaths a year in the UK alone and are the main cause for hospitalisation for suffers of asthma. The most common trigger for asthma attacks is the common cold virus (rhinovirus). Currently available therapies fail to prevent virus-induced asthma attacks and asthmatic patients desperately need an effective, preventative treatment for this. In light of the recognised relationship between rhinovirus and asthma attacks, an experimental model has been developed to study this association more closely. This involves inoculating asthmatics with rhinovirus via a spray in the nose under controlled conditions and allows the study of novel therapies. Due to careful selection of asthmatics without severe disease or a history of hospitalisation due to virus infections we have successfully used this model in over 50 asthmatics in a number of studies with great success. Unfortunately the only alternative option for studying asthma attacks (and the effect of therapies on them) is to recruit several hundred asthmatics and wait for asthma attacks to occur naturally. Such studies cost in excess of £30 million to conduct given the length of the study and the number of patients needed for recruitment (in order to capture enough attacks). The human experimental rhinovirus infection model therefore allows the study of asthma attacks and any treatment effects in a short amount of time and at a fraction of the cost. A molecule known as prostaglandin D2 (PGD2 )has been shown to be a very important link in the pathway of inflammation known as 'type 2 immunity'. This pathway underlies many of the symptoms that asthmatics develop including breathlessness, cough, chest tightness and wheeze and has been shown to be particularly high in severe asthmatics. We have shown in a recent study using the human rhinovirus model that this type of inflammation (including prostaglandin D2) is increased by rhinovirus in the airway during the virus-induced asthma attack and correlates strongly with the severity of the attack. Therefore blocking this molecule should halt the type 2 inflammation caused by the virus infection and limit the consequences of infection to simply a runny nose and a sore throat (as per non-asthmatic individuals) rather than the potentially life-threatening chest symptoms seen in asthma.Fortunately several drug companies have already developed a drug that blocks the prostaglandin D2 receptor known as 'CRTH2' but none have taken the step to study its effect in preventing asthma exacerbations. Importantly, these drugs have already been trialled in a number of short studies involving several hundred asthmatics and shown to have an excellent safety profile. Additionally these studies have highlighted this type of therapy as very good at suppressing the asthmatic airway inflammation downstream of PGD2. Based on our own research findings of a rhinovirus-induced increase in PGD2, we wish to assess the effect of blocking PGD2 using the CRTH2 receptor blocker 'OC459' in the context of a controlled rhinovirus-induced asthma attack. We have established that a study numbering 28 asthmatics, randomly assigned to either the drug or placebo would be sufficient to identify any benefit of this therapeutic approach to asthma care.

仅在英国，哮喘发作每年就导致 1000 多人死亡，也是哮喘患者住院的主要原因。哮喘发作最常见的诱因是普通感冒病毒（鼻病毒）。目前可用的疗法无法预防病毒引起的哮喘发作，哮喘患者迫切需要有效的预防性治疗。鉴于鼻病毒和哮喘发作之间公认的关系，已经开发了一种实验模型来更密切地研究这种关联。这涉及在受控条件下通过鼻喷雾给哮喘患者接种鼻病毒，并允许研究新疗法。由于仔细选择了没有严重疾病或因病毒感染住院史的哮喘患者，我们已在多项研究中成功地将这种模型应用于 50 多名哮喘患者，并取得了巨大成功。不幸的是，研究哮喘发作（以及治疗效果）的唯一选择是招募数百名哮喘患者并等待哮喘发作自然发生。考虑到研究的长度和招募所需的患者数量（为了捕获足够的攻击），此类研究的成本超过 3000 万英镑。因此，人类实验性鼻病毒感染模型可以在短时间内以较低的成本研究哮喘发作和任何治疗效果。一种称为前列腺素 D2 (PGD2) 的分子已被证明是称为“2 型免疫”的炎症途径中非常重要的一环。该通路是哮喘患者出现的许多症状的基础，包括呼吸困难、咳嗽、胸闷和喘息，并且已被证明在严重哮喘患者中特别高。我们最近使用人类鼻病毒模型进行的一项研究表明，在病毒引起的哮喘发作期间，气道中的鼻病毒会加剧这种类型的炎症（包括前列腺素 D2），并且与发作的严重程度密切相关。因此，阻断这种分子应该可以阻止病毒感染引起的 2 型炎症，并将感染的后果限制为简单的流鼻涕和喉咙痛（对于非哮喘个体），而不是哮喘中出现的潜在危及生命的胸部症状。幸运的是，几家制药公司已经开发出一种阻断前列腺素 D2 受体的药物，称为“CRTH2”，但没有一家公司采取措施研究其预防哮喘的效果。 病情加重。重要的是，这些药物已经在涉及数百名哮喘患者的多项短期研究中进行了试验，并显示出良好的安全性。此外，这些研究强调这种类型的疗法非常有效地抑制 PGD2 下游的哮喘气道炎症。根据我们自己对鼻病毒诱导的 PGD2 增加的研究结果，我们希望评估在受控鼻病毒诱导的哮喘发作的情况下使用 CRTH2 受体阻断剂“OC459”阻断 PGD2 的效果。我们已经确定，一项对 28 名哮喘患者进行的研究，随机分配到药物组或安慰剂组，足以确定这种治疗方法对哮喘护理的任何益处。

项目成果

Effect of CRTH2 antagonism on the response to experimental rhinovirus infection in asthma: a pilot randomised controlled trial.

• DOI: 10.1136/thoraxjnl-2021-217429
• 发表时间: 2022-10
• 期刊: Thorax
• 影响因子: 10

Comparative Metabolomic Sampling of Upper and Lower Airways by Four Different Methods to Identify Biochemicals That May Support Bacterial Growth

• DOI: 10.3389/fcimb.2018.00432
• 发表时间: 2018-12-18
• 期刊: FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
• 影响因子: 5.7
• 作者: Farne, Hugo;Groves, Helen T.;Tregoning, John S.
• 通讯作者: Tregoning, John S.

The CRTH2 Antagonist Timapiprant Does Not Alter the Response Rhinovirus Infection in Asthma: A Randomized, Placebo-Controlled Trial

CRTH2 拮抗剂 Timapiprant 不会改变哮喘中鼻病毒感染的反应：一项随机、安慰剂对照试验

• 发表时间: 2020
• 期刊: AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
• 影响因子: 24.7
• 作者: Farne H.

Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation.

• DOI: 10.1038/nm.4332
• 发表时间: 2017-06
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Toussaint M;Jackson DJ;Swieboda D;Guedán A;Tsourouktsoglou TD;Ching YM;Radermecker C;Makrinioti H;Aniscenko J;Bartlett NW;Edwards MR;Solari R;Farnir F;Papayannopoulos V;Bureau F;Marichal T;Johnston SL
• 通讯作者: Johnston SL

Evaluation of the Abbott Architect, Roche Elecsys and Virtus S1 SARS-CoV-2 antibody tests in community-managed COVID-19 cases

对社区管理的 COVID-19 病例中 Abbott Architect、Roche Elecsys 和 Virtus S1 SARS-CoV-2 抗体测试的评估

• DOI: 10.1101/2020.10.27.20220509
• 发表时间: 2020
• 作者: Johnston S