CardioTwin HCM: A non-genetic early diagnostic test for hypertrophic cardiomyopathy risk

项目摘要-该项目将验证一种新的肥厚检测方法--心脏双胞胎HCM 心肌病(HCM)风险，将为基因组- 基于诊断的诊断失败。当一个原本健康的年轻人突然死亡时，最 可能的原因是一种被称为肥厚型心肌病的遗传性心脏病。疾病的流行 一般人群的红细胞压积为~1：500，包括未确诊的个体。如果在一个家庭中发现人型多发性硬化症 成员，可以为他们的亲属采取救生预防措施。不幸的是，识别风险 家庭成员及早介入是困难的，有时甚至是不可能的。基因测序是 家族性巨细胞瘤筛查的现行临床标准。如果在肥厚型心肌炎患者中发现已知的突变，它可能 被用作识别高危家庭成员的标记--但这种情况只发生在大约50%的索引病例中。一个 不依赖于遗传学来预测HCM风险的筛查工具将覆盖到另外50%的家庭， 大幅改进预防性治疗，降低医疗费用和家庭成员的焦虑，以及 防止死亡。在以前的工作中，工程化心脏组织(EHTS)是用诱导多能性 来自三个已知携带常染色体显性突变的HCM患者的干细胞(IPSCs)。在……里面 与EHTS相比，患者来源的EHTS表现出更强的收缩强度和持续时间 由健康的个体制成。因此，这种“收缩特征”似乎是一个强健的表型标记。 胡志明市。我们用专有技术简化了这种EHT方法，以创建心脏双胞胎HCM：A 用于测量收缩信号的健壮而高效的系统。为了证明心脏双胞胎HCM可以使用 为了准确诊断，我们将对肥厚型心肌病患者细胞系和非肥厚型心肌病对照进行盲法研究。如果 事实证明，心脏双胞胎HCM将是第一个绕过基因测试陷阱的HCM诊断。 心脏病专家将在基因测试不确定的情况下使用这种测试，使大约97.5万美国人能够 基因测试不确定的情况下，最终将对HCM风险进行筛查。长期目标是心脏双胞胎HCM 成为基因检测不确定的HCM家庭风险评估的关爱标准。 这个第一阶段项目的具体目标是证明心脏双胞胎HCM测试可以正确地 在盲目患者队列中诊断肥厚型心肌炎。四个随机选择的肥厚型心肌炎患者IPSC系和四个 将从一个商业生物库获得额外的非HCM控制线，并将其通过心脏双胞胎 HCM测试程序。那些收缩信号明显改变的人将被标记为HCM阳性。 样本的身份将是非盲目的，并将计算心脏双胞胎HCM的敏感性和特异性。 达到总体敏感度加上特异度将标志着HCM风险评估方面的突破， 表明非遗传方法是可能的，并证明第二阶段资金是合理的。在第二阶段，普罗普里亚将 将盲测扩大到30人的队列，同时优化生产以达到成本可行性。由我们的 据估计，美国市场上有975,000例心脏双胞胎HCM检测。

PROJECT SUMMARY – This project will validate CardioTwin HCM, a new test for hypertrophic cardiomyopathy (HCM) risk that will provide life-saving diagnostic information for families in whom genome- based diagnostics have failed. When sudden death occurs in an otherwise healthy young person, the most likely cause is a form of inherited cardiac disease known as hypertrophic cardiomyopathy. The prevalence of HCM in the general population is ~1:500, including undiagnosed individuals. If HCM is discovered in one family member, life-saving preventative measures can be taken for their relatives. Unfortunately, identifying at-risk family members early enough to intervene is difficult and sometimes impossible. Genetic sequencing is the current clinical standard for HCM screening in families. If a known mutation is found in an HCM patient, it can be used as a marker to identify at-risk family members - but this happens in only ~50% of index cases. A screening tool that does not rely on genetics for predicting HCM risk would reach the other 50% of families, drastically improving preventative therapy, reducing healthcare costs and anxiety in family members, and preventing deaths. In previous work, engineered heart tissues (EHTs) were made using induced pluripotent stem cells (iPSCs) from three different patients known to carry an autosomal dominant mutation for HCM. In each case, patient-derived EHTs exhibited increased strength and duration of contractions compared to EHTs made from healthy individuals. This “contraction signature” thus appears to be a robust phenotypic marker of HCM. We have streamlined this EHT approach with proprietary technology to create CardioTwin HCM: a robust and efficient system for measuring contractile signatures. To prove that CardioTwin HCM can be used as an accurate diagnostic, we will conduct a blinded study on HCM patient cell lines and non-HCM controls. If proven, CardioTwin HCM would the first HCM diagnostic to circumvent the pitfalls of genetic testing. Cardiologists will use this test when genetic testing is inconclusive, enabling the roughly 975,000 Americans with inconclusive genetic tests to finally be screened for HCM risk. The long-term goal is for CardioTwin HCM to become the standard of care for risk evaluation in HCM families for whom genetic testing is inconclusive. The specific aim of this Phase I project is to demonstrate that the CardioTwin HCM test can correctly diagnose HCM in a blinded patient cohort. Four randomly selected HCM patient iPSC lines and four additional non-HCM control lines from a commercial biobank will be obtained and put through the CardioTwin HCM testing procedure. Those with significantly altered contraction signatures will be flagged as HCM-positive. The sample identities will be unblinded and the sensitivity and specificity of CardioTwin HCM will be computed. Achieving aggregate sensitivity plus specificity >1.5 would signal a breakthrough in HCM risk assessment, showing that a non-genetic approach is possible and justifying Phase II funding. In Phase II, Propria will expand blinded testing to a cohort of 30 individuals while optimizing production to reach cost feasibility. By our estimate, the US market for CardioTwin HCM is 975,000 tests.