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HCM双胞胎HCM，一种新的肥大性检查 心肌病（HCM）的风险，这将提供挽救生命的诊断信息的家庭，其中基因组- 基于的诊断失败。当一个健康的年轻人突然死亡时， 可能的原因是一种遗传性心脏病，称为肥厚型心肌病。之时尚 一般人群中的HCM约为1：500，包括未确诊的个体。如果在一个家庭中发现HCM， 成员，可以为他们的亲属采取救生预防措施。不幸的是， 家庭成员很难及早干预，有时甚至不可能。基因测序是 目前的临床标准，HCM筛查的家庭。如果在HCM患者中发现已知的突变， 作为一个标记，以确定在危险的家庭成员-但这只发生在约50%的索引案件。一 不依赖遗传学来预测HCM风险的筛查工具将覆盖另外50%的家庭， 大大改善预防性治疗，降低医疗费用和家庭成员的焦虑， 防止死亡。在以前的工作中，工程心脏组织（EHTs）是使用诱导多能 干细胞（iPSC）来自三个不同的患者，已知携带HCM的常染色体显性突变。在 在每种情况下，与EHT相比，患者源性EHT表现出收缩强度和持续时间增加 由健康的个体制成。因此，这种“收缩特征”似乎是一种强有力的表型标记， HCM。我们利用专有技术简化了EHT方法，以创建EHT Twin HCM： 用于测量收缩特征的稳健且高效的系统。为了证明双胞胎HCM可以用于 作为准确的诊断，我们将对HCM患者细胞系和非HCM对照进行盲法研究。如果 事实证明，双胞胎HCM将是第一个HCM诊断，以规避基因检测的陷阱。 心脏病专家将在基因测试不确定时使用这种测试，使大约975，000名美国人能够在2008年获得基因测试结果。 通过不确定的基因测试来最终筛查HCM风险。长期目标是实现双胞胎HCM 成为HCM家庭风险评估的标准护理，对他们来说，基因检测是不确定的。 这个第一阶段项目的具体目标是证明，双胞胎HCM测试可以正确地 在盲法患者队列中诊断HCM。四个随机选择的HCM患者iPSC系和四个 将从商业生物库中获得额外的非HCM对照线，并将其通过双胞胎 HCM测试程序。那些具有显著改变的收缩特征的人将被标记为HCM阳性。 将揭盲样本标识，并计算双胞胎HCM的灵敏度和特异性。 实现总灵敏度加特异性>1.5将标志着HCM风险评估的突破， 这表明非遗传方法是可能的，并证明了第二阶段的资金。在第二阶段，Propria将 将盲法测试扩大到30人的队列，同时优化生产以达到成本可行性。由我们 据估计，美国市场的双胞胎HCM是975，000测试。