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Using Genetics For Early Phenotyping & Prevention of Hypertrophic Cardiomyopathy

利用遗传学进行早期表型分析

基本信息

批准号：
8251351
负责人：
Carolyn Y Ho
金额：
$ 239.52万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8251351
关键词：
Adult Age Angiotensin II Receptor Animal Model Arrhythmia Attenuated Biochemistry Biological Markers Calcium Cardiac Cardiovascular Diseases Characteristics Clinical Clinical Trials Collagen DNA Data Development Diagnosis Diltiazem Disease Disease Progression Double-Blind Method Drops Early Diagnosis Early treatment Exercise Failure Fibrosis Fostering Frequencies Functional disorder Future Gender Genes Genetic Genetic Predisposition to Disease Genetic screening method Genotype Guidelines Heart Diseases Heart failure Hereditary Disease Human Hypertrophic Cardiomyopathy Hypertrophy Image Incidence Individual Injury Instruction Investigation Knowledge Lead Left Left Ventricular Hypertrophy Losartan Magnetic Resonance Medicine Methods Metric Modification Molecular Monitor Mus Mutation Myocardial Pathogenesis Pathology Pathway Analysis Patient Selection Pharmaceutical Preparations Phase Phenotype Physical activity Placebo Control Placebos Population Populations at Risk Prevention Puberty Quality of life Randomized Randomized Clinical Trials Reaction Relaxation Rest Risk Role Safety Sarcomeres Serum Staging Stress Structure Sudden Death Surrogate Endpoint Thick Time TimeLine Tissues Transforming Growth Factor beta Translations Ventricular Work arm base clinical Diagnosis design disease natural history fibrogenesis fundamental research human disease improved inhibitor/antagonist insight interstitial mouse model mutation carrier neutralizing antibody novel novel therapeutics pre-clinical prevent response secondary outcome success treatment effect treatment response

项目摘要

DESCRIPTION (provided by applicant): Discovering the genetic basis of human heart disease presents a remarkable opportunity to predict and prevent disease. By identifying at-risk individuals prior to clinical diagnosis and fostering development of novel therapies to delay or prevent clinical expression, genetic discoveries can transform medicine. Hypertrophic cardiomyopathy (HCM) provides a paradigm for fulfilling this opportunity. HCM is the most common monogenic cardiovascular disorder and is caused by dominant mutations in sarcomere genes. Clinical characteristics include left ventricular hypertrophy (LVH), myocardial fibrosis, diastolic dysfunction, and an increased risk for arrhythmias, sudden death and heart failure. Unexplained LVH, the defining clinical feature of HCM, is a relatively late manifestation of disease and typically emerges around the time of puberty. In contrast, gene-based diagnosis identifies not only individuals who carry pathogenic mutations (G+) and have overt disease (LVH+), but also at-risk G+ individuals who have not yet developed a clinical diagnosis of HCM (LVH-). Our investigations of G+/LVH- preclinical HCM subjects have identified novel early phenotypes in this important subset, thus providing insight into the initial consequences of sarcomere mutations and disease pathogenesis. Impaired LV relaxation and increased myocardial collagen synthesis both precede the onset of LVH. Furthermore, preclinical mutation carriers are a unique at-risk population to target therapies to prevent disease progression. Promising work in animal models has shown that early pharmacologic therapy can counteract the effect of pathogenic sarcomere mutation and diminish the emergence of HCM. Molecular network analysis in mouse models of HCM identified a central role for transforming growth factor-beta (TGFb) activation in myocardial fibrogenesis. Administration of neutralizing antibody or angiotensin II receptor blockade to inhibit TGF-b activation in prehypertrophic HCM mice was associated with less development of hypertrophy and fibrosis compared with placebo. Collectively these data suggest considerable benefit from defining genetic susceptibility and intervening early in HCM. Through our 2-stage CTRIP studies, we will foster clinical translation of these key scientific discoveries, culminating in a Phase II multicenter, doubleblind, placebo-controlled randomized clinical trial to assess the safety and efficacy of the potent ARB, candesartan, in attenuating disease progression, using early phenotypes as surrogate endpoints to monitor treatment response. With these efforts, we will begin to reshape the clinical paradigm for treating adult-onset genetic disorders, based on early diagnosis, mechanistic insight, and disease modification. RELEVANCE: Fundamental research discoveries have provided critical insight into how subtle changes in our DNA lead to the dramatic changes in cardiac structure and function that characterize HCM. This knowledge can enable new therapeutic strategies to interrupt pathogenesis. Clinical translation of these breakthroughs will lead to a future when genetic destiny can be changed. Early treatment can be targeted to at-risk, genetically susceptible individuals to offset the consequences of pathogenic mutations and prevent disease progression.

描述（由申请人提供）：发现人类心脏病的遗传基础为预测和预防疾病提供了一个绝佳的机会。通过在临床诊断之前识别有风险的个体，并促进新疗法的开发以延迟或防止临床表现，遗传发现可以改变医学。肥厚型心肌病（HCM）为实现这一机会提供了一个范例。HCM是最常见的单基因心血管疾病，由肌节基因的显性突变引起。临床特征包括左心室肥大（LVH）、心肌纤维化、舒张功能障碍以及心律失常、猝死和心力衰竭风险增加。原因不明的左心室肥厚是肥厚型心肌病的临床特征，是一种相对较晚的疾病表现，通常在青春期左右出现。相比之下，基于基因的诊断不仅可以识别携带致病性突变（G+）和明显疾病（LVH+）的个体，还可以识别尚未发展出HCM临床诊断（LVH-）的G+风险个体。我们对G+/LVH-临床前HCM受试者的研究已经在这一重要子集中鉴定了新的早期表型，从而提供了对肌节突变和疾病发病机制的初步结果的深入了解。左室舒张功能受损和心肌胶原合成增加均先于LVH的发生。此外，临床前突变携带者是靶向治疗以防止疾病进展的独特风险人群。在动物模型中有希望的工作表明，早期药物治疗可以抵消致病性肌节突变的影响，减少HCM的出现。HCM小鼠模型的分子网络分析确定了转化生长因子β（TGF β）激活在心肌纤维化中的核心作用。与安慰剂相比，给予中和抗体或血管紧张素II受体阻断剂以抑制肥大前期HCM小鼠中TGF-β的活化与较少的肥大和纤维化发展相关。总的来说，这些数据表明，确定遗传易感性和早期干预HCM有相当大的好处。通过我们的2阶段CTRIP研究，我们将促进这些关键科学发现的临床转化，最终完成一项II期多中心、双盲、安慰剂对照随机临床试验，以评估强效ARB坎地沙坦在减缓疾病进展方面的安全性和疗效，使用早期表型作为替代终点来监测治疗反应。通过这些努力，我们将开始重塑治疗成人发病遗传性疾病的临床范式，其基础是早期诊断、机制洞察和疾病修饰。相关性：基础研究的发现为我们的DNA的细微变化如何导致HCM特征的心脏结构和功能的巨大变化提供了重要的见解。这些知识可以使新的治疗策略中断发病机制。这些突破的临床转化将导致一个基因命运可以改变的未来。早期治疗可以针对有风险的遗传易感个体，以抵消致病性突变的后果并防止疾病进展。