STTR Phase I: Developing a platform for superior predictive analysis of HERG Ion Channel-Drug Interactions for the Comprehensive In-vitro Proarrhythmia Assay (CiPA)

这个小企业技术转让（STTR）项目的更广泛的影响/商业潜力将是改善FDA批准的新药的安全性测试。 通过减少与安全性测试相关的时间和成本，该产品将使所有类别的新药更安全，更便宜，更快地提供给患者。 所有新药都必须证明它们是安全的。 新的候选治疗失败的一个常见和关键点是因为它们具有通过致命的心律失常促进心脏性猝死的严重副作用。该产品将先进的生物技术与先进的计算技术相结合，开发出一种系统，使制药和生物技术公司能够在开发过程的早期更快速、更准确地识别出药物，从而为制药公司节省了与药物开发相关的大量成本。最终未能通过心脏安全筛选的药物需要尽快从开发管道中淘汰，当然是临床前。在确定心脏副作用之前进行临床试验的药物除了人力成本外，还可能导致大量浪费成本。相反，错误淘汰的药物也可能是昂贵的，无论是在损失的收入和对社会的利益方面。这个STTR第一阶段是一个建议，以改善从HERG离子通道的实验中提取关键数据，并通过新的FDA CiPA计划中的计算建模对其进行解释。临床前安全性测试目前集中在两个相互依赖的问题：1）药物是否阻断HERG通道？2）药物是否延长动作电位？CiPA倡议建议通过在高通量系统中筛选一组定义的克隆离子通道，并通过qNet指数将其与动作电位建模相结合，系统地整合这一过程。HERG通道使用复杂的状态依赖块模型单独处理，由于其复杂性，需要非常困难和耗时的手动测量。该提案将通过使用计算机模型块的实时接口来自动化该过程，并在电压钳实验发生时评估来自电压钳实验的信息。 因此，它将是一个人工智能，将取代人类实验人员的判断，只关注定义特定药物动力学的协议和暴露时间。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

The broader impact/commercial potential of this Small Business Technology Transfer (STTR) project will be to improve the safety testing of new drugs for approval by the FDA. By decreasing the time and costs associated with safety testing, the product will make all classes of new drugs safer, less expensive and available to patients sooner. All new drugs must demonstrate that they are safe. One common and critical point at which new candidate treatments fail is because they have the serious side effect of promoting sudden cardiac death through lethal arrhythmias. This product combines advanced biological techniques with advanced computing to develop a system that will enable pharma and biotech companies to more rapidly and accurately identify pro-arrhythmic drugs earlier in the development process, thus saving drug companies significant costs associated with drug development. Drugs that ultimately fail cardiac safety screening need to be eliminated as soon as possible from the development pipeline, and certainly pre-clinically. A drug that makes it to clinical trials before cardiac side effects are identified can result in significant wasted costs, in addition to the human cost. Conversely, a drug incorrectly eliminated also can be costly, both in terms of lost revenue and benefit to society.This STTR Phase I is a proposal to improve the extraction of key data from experiments on the HERG ion channel and its interpretation through computational modeling in the new FDA CiPA initiative. Preclinical safety testing currently focuses on two interdependent questions: 1) Does the drug block the HERG channel? and 2) Does the drug prolong the action potential? The CiPA initiative proposes to integrate this process systematically, through screening of a defined set of cloned ion channels in high throughput systems and combing this with action potential modelling through the qNet index. The HERG channel is handled separately using a complex state-dependent block model that due to its complexity requires very difficult and time consuming manual measurements. This proposal will automate this process by using a real-time interface to computer model block and evaluate the information coming from voltage clamp experiments as they occur. As such it will be an artificial intelligence that will substitute for the judgement of a human experimenter by focusing only on protocols and exposure times that define the kinetics of a particular drug.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.