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：
9122444
负责人：
Carolyn Y Ho
金额：
$ 219.83万
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 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9122444
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 Incidence Individual Injury Instruction Investigation Knowledge Lead Left Left Ventricular Hypertrophy Losartan Magnetic Resonance Medicine Methods 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 cardiovascular visualization clinical Diagnosis coronary fibrosis design disease natural history fibrogenesis fundamental research human disease improved inhibitor/antagonist insight interstitial mouse model mutation carrier neutralizing antibody novel novel therapeutic intervention novel therapeutics pre-clinical prevent response secondary outcome success targeted treatment treatment effect treatment group 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 (TGFß) activation in myocardial fibrogenesis. Administration of neutralizing antibody or angiotensin II receptor blockade to inhibit TGF-ß 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.

描述（适用提供）：发现人心脏病的遗传基础是预测和预防疾病的非凡机会。通过在临床诊断之前鉴定高危人群并促进新疗法的发展以延迟或预防临床表达，遗传发现可以改变医学。肥厚的心肌病（HCM）为实现这一机会提供了一个范式。 HCM是最常见的单基质性心血管疾病，是由肉瘤基因中的显性突变引起的。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不齐，猝死和心力衰竭的风险增加。无法解释的LVH是HCM的定义临床特征，是疾病的相对晚期表现，通常在青春期左右出现。相比之下，基于基因的诊断不仅鉴定了携带致病性突变（G+）并患有明显疾病（LVH+）的个体，而且还鉴定了尚未开发出HCM临床诊断的高危G+个体（LVH-）。我们对G+/LVH-临床前HCM受试者的研究已经确定了这一重要子集中的新型早期表型，从而洞悉了肌节突变和疾病发病机理的最初后果。 LV松弛受损并增加了心肌胶原蛋白合成，这既先于LVH的发作。此外，临床前突变载体是靶向预防疾病进展的独特危险人群。动物模型中有前途的工作表明，早期的药物治疗可以抵消致病性肌节突变的作用并减少HCM的出现。 HCM小鼠模型中的分子网络分析确定了在心肌纤维发生中转化生长因子-BETA（TGFß）激活的核心作用。与安慰剂相比，中和性抗体或血管紧张素II受体阻断抑制抑制性植物前HCM小鼠的TGF-ß活化与肥大和纤维化的发育较小有关。这些数据共同提出了定义遗传易感性和在HCM早期介入的可能益处。通过我们的2阶段CTRIP研究，我们将培养这些关键科学发现的临床翻译，最终在II期多中心，双重蓝色，安慰剂控制的随机临床试验中，以减弱早期的现象型在替代治疗方法中，以评估潜在ARB，Candesartan的潜在ARB的安全性和效率。通过这些努力，我们将根据早期诊断，机械洞察力和疾病修饰来重塑治疗成人发作遗传疾病的临床范式。