Towards a better understanding of the human heart: development of a predictive in vitro model of cardiac safety

该项目旨在开发和验证使用人类心脏细胞和组织体外预测心脏副作用的方法。药物引起的心脏安全性问题是药物开发行业的主要关注点，这不仅是因为涉及心脏的并发症的严重性，而且还因为在发现心脏安全性问题时可能丢失潜在有价值的药物。几种药物在药物诱发心律失常的情况下已从市场上撤回，许多更常用的药物与短期促心律失常作用（例如胺碘酮、特非那定、西沙必利）或对心脏功能的长期有害作用（蒽环类药物，如多柔比星）相关。在药物安全理事会最近的一项调查中，制药公司内的安全药理学家和毒理学家将其最优先的创新技术评为“体外心血管风险”。这项调查还强调了现有的基于细胞和体内动物试验的明显缺点，以及监管机构要求更加重视更新的更具预测性的心血管风险模型。Biopta旨在通过扩大其目前对人类心血管分离组织的测试来解决这一机会，以包括专门针对主要药物相关的促血管活性风险的心脏安全性测试。第二个目标将是确定组织健康和功能的标志物，这些标志物可能表明与细胞应激相关的长期风险。学生将致力于开发使用人体心室和心房组织的方法，以更好地预测药物诱导心律失常的风险。目前的方法是费力的，技术上具有挑战性，并依赖于立即从患者身上获得的组织。此外，通量是一个问题，因为组织不能存活足够长的时间，并且组织样品也不能产生足够的测试条件。这些因素限制了人体组织的使用，尽管人体组织被接受为黄金标准测试系统。该项目旨在通过开发更有效的运输和储存条件来延长新鲜组织的寿命，并将寻求最大限度地减少每次检测所需的组织数量。此外，该项目还将调查人体组织之间的变异性以及不同人群/患者群体对已知可诱发心律失常效应的药物的反应，以改善预测并提供更好的护理。除了减少药物开发所需的时间和成本外，创建这种预测性体外模型确实符合英国研究委员会的优先事项，即减少在研究中使用动物和体内实验。Biopta此前获得了NC 3Rs基金的小额赠款，用于开发胃肠道功能研究的替代方法和在肿瘤功能模型中使用人体组织。然而，该项目的主要目标是开发一种新的有效方法来预测心血管风险。

The project aims to develop and validate methods for the in vitro prediction of cardiac side-effects using human cardiac cells and tissues. Drug-induced cardiac safety issues are a major concern of the drug development industry not only because of the severity of complications involving the heart but also because of the possibility that potentially valuable drugs are lost upon the discovery of cardiac safety issues. Several drugs have been withdrawn from the market following instances of drug-induced arrhythmia and many more commonly used drugs are associated with short-term pro-arrhythmic effects (e.g. amiodarone, terfenadine, cisapride) or longer term deleterious effects on heart function (anthracyclines such as doxorubicin). In a recent survey by the Drug Safety Council, safety pharmacologist and toxicologists within pharmaceutical companies rated their highest priority innovative technologies to be 'in vitro cardiovascular risk'. This survey also highlighted the perceived shortcomings of existing cell-based and in vivo animal tests and requests from regulatory bodies for greater emphasis to be placed on newer more predictive models of cardiovascular risk. Biopta aims to address this opportunity by expanding its current tests of human cardiovascular isolated tissues to include cardiac safety tests that specifically address the main drug-related risk of pro-arrhythmic activity. A secondary objective will be to identify markers of tissue health and function that may indicate long-term risks related to cell stress. The student will aim to develop methods using human ventricular and atrial tissues in order to better predict the risk of drugs inducing arrhythmia. Current methods are laborious, technically challenging and dependent on tissue obtained immediately from patients. Furthermore, throughput is a problem because tissues do not survive long enough and neither do the tissue samples generate enough test conditions. These factors have limited the use of human tissue, despite human tissue being accepted as a gold standard test system. The project will aim to extend the lifespan of fresh tissues through the development of more effective transport and storage conditions and will seek to minimise the amount of tissue required for each assay. In addition the project will investigate variability between human tissues and responses of different populations/patient groups to drugs known to induce pro-arrythmic effects in order to improve prediction and provide better care. In addition to reducing time and costs involved in drug development, the creation of such predictive in vitro models does fit with the priority of UK research councils to reduce the use of animals and in vivo experiments in research. Biopta previously received small grant from the NC3Rs fund to develop alternative methods for the study of gastrointestinal function and the use of human tissues in models of tumour function. The main goal of the project, however, is to develop a novel validated method for predicting cardiovascular risk.