Using Genetics For Early Phenotyping & Prevention of Hypertrophic Cardiomyopathy

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）活化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。

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.