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绝佳的机会。通过在临床诊断前识别高危个体并促进新疗法的开发以延迟或阻止临床表达，基因发现可以改变医学。肥厚型心肌病（HCM）为实现这一机会提供了范例。 HCM 是最常见的单基因心血管疾病，由肌节基因显性突变引起。临床特征包括左心室肥厚（LVH）、心肌纤维化、舒张功能障碍以及心律失常、猝死和心力衰竭的风险增加。不明原因的 LVH 是 HCM 的典型临床特征，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+) 和患有明显疾病 (LVH+) 的个体，还可以识别尚未进行 HCM 临床诊断 (LVH-) 的高危 G+ 个体。我们对 G+/LVH- 临床前 HCM 受试者的研究已经在这个重要的子集中识别出新的早期表型，从而深入了解肌节突变和疾病发病机制的最初后果。左心室舒张受损和心肌胶原合成增加均先于左心室肥厚发生。此外，临床前突变携带者是独特的高危人群，需要针对性治疗以预防疾病进展。动物模型中的前景广阔的研究表明，早期药物治疗可以抵消致病性肌节突变的影响并减少 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 (TGFb) 激活在心肌纤维形成中的核心作用。与安慰剂相比，在肥大前期 HCM 小鼠中施用中和抗体或血管紧张素 II 受体阻断剂来抑制 TGF-b 激活，可减少肥厚和纤维化的发生。总的来说，这些数据表明，确定遗传易感性和早期干预 HCM 具有相当大的益处。通过我们的两阶段 CTRIP 研究，我们将促进这些关键科学发现的临床转化，最终进行 II 期多中心、双盲、安慰剂对照随机临床试验，以评估强效 ARB 坎地沙坦在减轻疾病方面的安全性和有效性进展，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，我们将开始在早期诊断、机制洞察和疾病修正的基础上重塑治疗成人发病遗传性疾病的临床范例。相关性：基础研究发现为了解 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能够中断发病机制。这些突破的临床转化将带来改变遗传命运的未来。早期治疗可以针对高危、遗传易感人群，以抵消致病突变的后果并防止疾病进展。