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

CardioTwin HCM：肥厚型心肌病风险的非遗传早期诊断测试

• 批准号: 10382593
• 负责人: Cassady E. Rupert
• 金额: $ 25.96万
• 依托单位: PROPRIA LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382593
• 关键词: Adoption; American; Anxiety; Behavior; Blinded; Blood specimen; CLIA certified; Cardiac; Cell Line; Cells; Cessation of life; Classification; Clinical; Diagnosis; Diagnostic; Diagnostic tests; Direct Costs; Disease; Early Diagnosis; Evaluation; Exhibits; Family; Family Sizes; Family member; First Degree Relative; Funding; General Population; Genetic; Genetic Markers; Genome; Goals; Health Care Costs; Heart Diseases; Hereditary Disease; Human Engineering; Hypertrophic Cardiomyopathy; Individual; Inherited; Intervention; Laboratories; Legal patent; Licensing; Life; Link; Measures; Medical; Mutation; Outcome; Patients; Persons; Phase; Population; Prevalence; Preventive measure; Preventive therapy; Procedures; Production; Research Project Grants; Risk; Risk Assessment; Sampling; Savings; Screening procedure; Sensitivity and Specificity; Signal Transduction; Small Business Innovation Research Grant; Specificity; Sudden Death; Sum; System; Technology; Testing; Time; Work; accurate diagnosis; accurate diagnostics; autosomal dominant mutation; base; biobank; cardiac tissue engineering; cohort; commercial application; cost; diagnostic accuracy; diagnostic signature; genetic predictors; genetic testing; improved; indexing; induced pluripotent stem cell; invention; non-genetic; phenotypic biomarker; precision medicine; predictive test; prevent; process optimization; screening; standard of care; stem cells; trait

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.

项目摘要 - 该项目将验证Cardiotwin HCM，这是一种针对肥厚型的新测试 心肌病（HCM）风险将为基因组的家庭提供挽救生命的诊断信息 基于的诊断失败了。当突然死亡发生在一个原本健康的年轻人中时，最多 可能原因是一种遗传性心脏病的一种形式，称为肥厚性心肌病。流行率 一般人群中的HCM为〜1：500，包括未诊断的个体。如果在一个家庭中发现了HCM 可以为其亲戚采取挽救生命的预防措施。不幸的是，确定高危 足够早的家庭成员很难进行干预，有时是不可能的。遗传测序是 家庭中HCM筛查的当前临床标准。如果在HCM患者中发现已知突变，则可以 被用作标记以识别高风险家庭成员 - 但这仅在约50％的索引案例中发生。一个 不依赖遗传学来预测HCM风险的筛查工具将到达其他50％的家庭， 大大改善预防疗法，降低家庭成员的医疗保健成本和焦虑，以及 防止死亡。在以前的工作中，使用诱导的多能进行工程心脏组织（EHT） 来自三名不同患者的干细胞（IPSC），已知携带HCM常染色体显性突变。在 与EHT相比 由健康的个体制成。因此，这种“收缩签名”似乎是强大的表型标记 HCM。我们已经用专有技术简化了这种EHT方法来创建Cardiotwin HCM： 衡量收缩签名的强大而有效的系统。证明可以使用Cardiotwin HCM 作为准确的诊断，我们将对HCM患者细胞系和非HCM对照进行盲目研究。如果 经过证明的是，Cardiotwin HCM将是第一个HCM诊断，以规避基因检测的陷阱。 当基因测试尚无定论时，心脏病专家将使用此测试，使大约97.5万美国人 最终将基因检测确定为HCM风险。长期目标是Cardiotwin HCM 成为基因检测尚无定论的HCM家族中风险评估的护理标准。 该阶段I项目的具体目的是证明Cardiotwin HCM测试可以正确 在盲人患者队列中诊断HCM。四个随机选择的HCM患者IPSC线和四个 将获得商业生物库的其他非HCM控制线，并通过Cardiotwin进行 HCM测试程序。那些收缩特征明显改变的人将被标记为HCM阳性。 样本身份将不盲目，并且将计算Cardiotwin HCM的灵敏度和特异性。 达到骨料灵敏度加上特异性> 1.5将表明HCM风险评估的突破， 表明非遗传方法是可能的，并证明了II期资金的合理性。在第二阶段，Provia将会 将盲试验扩展到30个人的队列，同时优化生产以达到成本可行性。由我们 估计，美国Cardiotwin HCM市场是975,000个测试。