Inhaled EP4 receptor agonists for the treatment of idiopathic pulmonary fibrosis

吸入EP4受体激动剂治疗特发性肺纤维化

• 批准号: MR/R025142/1
• 负责人: Steven Charlton
• 金额: $ 87.53万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR025142%2F1
• 关键词: Inhaled; EP4; receptor; agonists; treatment

This project aims to deliver a novel drug candidate for the treatment of idiopathic pulmonary fibrosis (IPF), a debilitating and fatal disease for which few treatment options are available. IPF is a chronic and progressive lung disease where excessive scarring occurs in the lung. This leads to stiffening of the airways, making it harder for the lungs to inflate and function normally, which causes severe shortness of breath. Patients with IPF experience worsening symptoms over time that prevent them performing activities that many of us take for granted, including daily tasks such as washing and dressing. For many people this progression is rapid, and people die early. In fact, with an average survival time of only 3 years from diagnosis, IPF is worse than most cancers. Diagnosis of IPF is a complex and lengthy process, but current estimates suggest that 18 people in every 100,000 suffer from it in the UK. Wound healing is a normal process where naturally occurring substances (or growth factors) in the lung stimulate regrowth of cells to repair the damaged area. For some reason, in IPF this process is not properly regulated, so cell growth continues unchecked resulting in the characteristic scarring of the lungs. Currently two anti-cancer drugs are used in IPF in an attempt to prevent this cell growth, but they only inhibit some of the growth factors that stimulate repair, so are not very effective. They are also swallowed drugs and have unwanted effects on other parts of the body. This is particularly bad in the gut where they can cause diarrhoea that is so severe that many patients chose to stop taking their medicines. Despite ongoing research in this area, effective medicines to treat IPF remain elusive, highlighting the need to explore new ways of treating this disease. We have identified a novel approach to treat IPF. By specifically activating beneficial pathways in lung cells we will counteract the unregulated wound healing stimulated by all growth factors involved in IPF. We will do this by switching on a particular protein on the surface of lung cells known as the EP4 receptor. We have already shown that activation of this receptor is able to robustly inhibit several key processes involved in scarring, and therefore has the potential to treat this debilitating disease. In addition to improving the effectiveness of existing IPF medicines, we also want to make them safer by reducing the severe side effects linked to them. To do this, we plan to develop a medicine that can be taken using an inhaler, similar to other lung diseases like asthma. This will allow us to deliver our medicine directly to the lung where they are needed, without reaching the rest of the body where they may cause unwanted effects. This project has been designed and submitted by researchers at the University of Nottingham who have significant expertise in making drugs for lung diseases, having successfully brought new drugs to market for asthma and chronic obstructive pulmonary disease (COPD). Our aim is to build on these successes and develop a novel, effective and safe medicine for IPF patients.

该项目旨在提供一种用于治疗特发性肺纤维化（IPF）的新型候选药物，IPF是一种衰弱和致命的疾病，几乎没有治疗选择。IPF是一种慢性和进行性肺部疾病，其中肺部出现过度瘢痕形成。这会导致气道变硬，使肺部更难正常充气和运作，从而导致严重的呼吸短促。IPF患者的症状会随着时间的推移而恶化，使他们无法进行我们许多人认为理所当然的活动，包括日常任务，如洗涤和穿衣。对于许多人来说，这种进展很快，人们会早逝。事实上，IPF的平均生存时间仅为3年，比大多数癌症更糟。IPF的诊断是一个复杂而漫长的过程，但目前的估计表明，在英国，每10万人中就有18人患有IPF。伤口愈合是一个正常的过程，其中肺中天然存在的物质（或生长因子）刺激细胞再生以修复受损区域。由于某些原因，在IPF中，该过程未得到适当调节，因此细胞生长继续不受抑制，导致肺部的特征性瘢痕形成。目前有两种抗癌药物用于IPF，试图阻止这种细胞生长，但它们只能抑制一些刺激修复的生长因子，因此不是很有效。它们也是吞服的药物，对身体的其他部位有不良影响。这在肠道中尤其糟糕，它们可能导致腹泻，严重到许多患者选择停止服用药物。尽管在这一领域正在进行研究，但治疗IPF的有效药物仍然难以捉摸，这突出表明需要探索治疗这种疾病的新方法。我们已经确定了一种治疗IPF的新方法。通过特异性激活肺细胞中的有益途径，我们将抵消IPF中涉及的所有生长因子刺激的不受调节的伤口愈合。我们将通过打开肺细胞表面的一种特殊蛋白质来实现这一点，这种蛋白质被称为EP4受体。我们已经证明，这种受体的激活能够有力地抑制与瘢痕形成有关的几个关键过程，因此有可能治疗这种使人衰弱的疾病。除了提高现有IPF药物的有效性外，我们还希望通过减少与之相关的严重副作用使其更安全。为此，我们计划开发一种可以使用吸入器服用的药物，类似于哮喘等其他肺部疾病。这将使我们能够将药物直接输送到需要它们的肺部，而不会到达身体的其他部位，因为它们可能会造成不必要的影响。该项目由诺丁汉大学的研究人员设计和提交，他们在制造肺部疾病药物方面具有重要的专业知识，成功地将哮喘和慢性阻塞性肺疾病（COPD）的新药推向市场。我们的目标是在这些成功的基础上，为IPF患者开发一种新型、有效和安全的药物。