PFI-TT: Automated Platform for Drug Testing in Human Heart Cells Using Light

这个PFI项目对美国经济和公共健康的更广泛的影响/商业潜力将通过为药物和干细胞研究人员和开发商提供一种先进但低成本的技术来检测对心脏的不利影响来实现，从而提供更便宜、更有效和更安全的药物治疗。药物开发费用昂贵(每种药物26亿美元)，是一个高风险的过程，在临床试验和市场批准之前对失败的评估不充分可能导致生命损失，给投资者带来巨大的经济损失，解雇员工，并可能外包给发展中国家。拟议的技术将改善早期临床前试验中的失败预测，未来商业化产品的采用将降低药物开发机会成本。它还将使追求更具挑战性的项目成为可能，包括个性化治疗和为特定患者群体量身定做的治疗，例如，在测试新的药物治疗时考虑性别、种族或其他特征。该技术背后的女性团队致力于成功地建立和发展一家公司，目标是帮助提高STEM相关创业领域的多样性，并成为来自所有背景的未来STEM企业家的盟友和榜样。拟议的项目将开发心脏电生理学基础和翻译工作的技术。它将通过产生有关心脏电功能障碍的高内容高质量信息，使潜在致命心律失常的机制研究成为可能，这与新的抗心律失常疗法的发现相关。光遗传学方法和光学成像的集成提供了高通量的功能评估，并使药物筛选中的个性化解决方案成为可能。该技术尚未满足的需求和优势包括与人类干细胞来源的心肌细胞和组织结构的兼容性，在收集多参数时空信息以更好地预测药物消耗的同时提供受控起搏条件，以及低成本。解决了转化为商业应用的以下挑战：1)确定低成本、紧凑且可通过用户友好型软件定制的独立原型的最佳光学配置；2)使用该系统为科学有效的(双盲和受控)分析设计建立工作流程；3)确定关键测量(生物标记物)和算法，以预测体外数据如何转化为体内临床结果(终点)。这将导致一个独立的原型，可以很容易地整合到现有的工作流程中，一个在盲目、对照研究中测试的化合物的扩展库，以及利用测量数据对心脏毒性风险进行分层的心律失常预测软件。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this PFI project on the economy and public health in the United States will be achieved by providing drug and stem-cell researchers and developers with a superior yet low-cost technology for detection of adverse effects on the heart to deliver cheaper, more effective, and safer drug treatments. Drug development is expensive ($2.6 billion per drug) and a high-risk process, where inadequate assessment of failures prior to clinical trials and market approval can result in loss of human life and come at great financial losses to investors, termination of employees, and potential outsourcing to developing countries. The proposed technology will improve failure prediction during early preclinical testing, where future adoption of the commercialized product will reduce drug development opportunity costs. It will also enable the pursuit of more challenging projects, including personalized therapies and therapies tailored for specific patient populations, e.g. considering sex, race or other characteristics when testing a new drug treatment. The female team behind the technology is committed to the successful establishment and growth of a company with a goal to help improve diversity in the STEM-related startup field, and serve as allies and role models for future STEM entrepreneurs from all backgrounds.The proposed project will develop technology for basic and translational work in cardiac electrophysiology. It will empower mechanistic studies of potentially lethal heart arrhythmias by yielding high-content high-quality information about cardiac electrical dysfunction, relevant for the discovery of new antiarrhythmic therapies. The integration of optogenetic methods and optical imaging offers high-throughput functional assessment and enables personalized solutions in drug screening. The unmet needs and advantages offered by the technology include compatibility with human stem-cell-derived cardiomyocytes and tissue constructs, provision of controlled pacing conditions while gathering multiparameter spatio-temporal information for better predictions of drug attrition, and low-cost. The following challenges in the translation to commercial applications are addressed: 1) determine the optimal optical configuration for a stand-alone prototype that is low-cost, compact, and customizable with user-friendly software; 2) establish the workflow for scientifically valid (double-blinded and controlled) assay designs using the system; 3) identify key measurements (biomarkers) and algorithms to predict how in vitro data translates to in vivo clinical outcomes (endpoints). This will result in a free-standing prototype that can be easily integrated into established workflows, an expanded library of compounds tested in a blinded, controlled study, and arrhythmia prediction software that utilizes measured data to stratify cardiotoxicity risk.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.