HLS-Cardiac Safety AI Trained Human Heart and Micro Heart Model

HLS17-12。美国FDA正在考虑建立一种新的心脏安全评估方法 由一种名为“全面体外心律失常分析(CIPA)”的新范式定义。这个 CIPA将1)单独评估药物对每种心脏离子通道类型的影响，使用高- 吞吐量分析离子通道分析，2)计算复极的净影响和风险 Torsade Points(TDP)使用数学模型，以及3)通过以下方式确认计算预测 测定药物对诱导多能干细胞(IPSC)动作电位的影响 人心肌细胞(CMS)。这一范式转变如果成功，可能会降低 通过替换或降低执行昂贵的(2-4美元) 百万)在临床试验期间进行全面的QT研究。保护消费者免受药物诱导 心律失常和猝死对监管机构和制药公司来说是最重要的 同时降低了药物开发的成本。 然而，许多心脏安全科学家对CIPA的方法持怀疑态度，因为CMS源于 来自人类的IPSCs由于其不成熟而表现出较差的兴奋-收缩偶联。在……里面 此外，还提出了一个模拟电生理的CIPA数学模型。 人类成人CMS，因此实验系统和计算工具之间存在不匹配。 为了解决这些担忧，我们提出了两个阶段的三个具体目标，即遵循FAST- 跟踪SBIR流程。第一阶段可行性目标1将衡量药物引起的AP和 猫使用从人类捐赠者身上分离出来的成人心脏切片。在这里我们将确认我们的 成功处理和分析人类成人心脏切片，这将基于最近的 由我们的合作者，乔治华盛顿大学的伊戈尔·埃菲莫夫博士发表的协议。在这之后 为了验证，我们将继续进行以下两项研究：目的2.比较药物诱导的 成人CMS和心脏成纤维细胞产生的NuHeart中AP和CAT的变化 同样的人类供体心脏；目标3.验证和改进计算模型并培训 人工智能预测未知化合物的心脏安全风险。 在我们圆满完成提出的项目后，我们可以建立一个前所未有的心脏 安全评估平台，可以使用训练有素的人工智能预测安全问题，而不需要 任何使用人体心脏切片的实验，这些切片在大多数情况下都是很难接触到的 实验室或生物技术公司。

HLS17-12. The US FDA is considering to establish a new cardiac safety assessment approach defined by a new paradigm called, “Comprehensive in vitro Proarrhythmia Assay (CIPA)”. The CIPA will 1) assess drug effects on each cardiac ion channel type individually using a high- throughput assay ion channel assays, 2) compute net effect on repolarization and risks for torsade pointes (TdP) using a mathematical model, and 3) confirm the computational prediction by measuring the drug’s effects on action potentials in induced pluripotent stem cell (iPSC) derived human cardiac myocytes (CMs). This paradigm shift, if successful, could reduce the cost of cardiac safety analyses by replacing or lowering the requirement to perform an expensive ($2-4 million) thorough QT study during clinical trials. Protecting consumers from drug induced arrhythmia and sudden deaths is a paramount importance for the regulators and pharmaceutical companies as well as lowing the cost of drug development. Many cardiac safety scientists, however, are skeptical about CIPA’s approach since CMs derived from human iPSCs exhibit a poor excitation-contraction coupling due to their immaturity. In addition, a proposed CIPA mathematical model was developed to simulate electrophysiology of human adult CMs, so there is a mismatch between experimental system and computational tool. To address these concerns, we proposed three specific aims in tw0 phases by following Fast- Track SBIR processes. Phase I feasibility Aim 1 will measure drug-induced changes in AP and CaT using human adult heart slices isolated from human donors. Here we will confirm our successful handling and analyzing human adult heart slices, which will be based on a recently published protocol by our collaborator, Dr. Igor Efimov, at George Washington University. After this validation, we will move on to perform the following two studies: Aim 2. Compare drug-induced changes in AP and CaT in NuHearts generated from adult CMs and cardiac fibroblasts from same human donor hearts; Aim 3. Validate and improve the computational models and train an artificial intelligence to predict cardiac safety risks of unknow compounds. After our successful completion proposed projects, we can establish an unprecedented cardiac safety assessment platform that can predict safety issues using a well-trained AI without doing any experiments using human heart slices that are rarely accessible for most of the safety laboratories or biotech firms.