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非凡的机会。通过在临床诊断之前识别高危个体，促进新疗法的发展以延缓或预防临床表达，基因发现可以改变医学。肥厚性心肌病（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，由肌瘤基因的显性突变引起。临床特征包括左心室肥厚（LVH）、心肌纤维化、舒张功能障碍、心律失常、猝死和心力衰竭的风险增加。不明原因LVH是HCM的决定性临床特征，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+）和显性疾病（LVH+）的个体，还可以识别尚未临床诊断为HCM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亚群中新的早期表型，从而为肉瘤突变和疾病发病机制的初始后果提供了见解。左室舒张受损和心肌胶原合成增加均先于左室血栓形成。此外，临床前突变携带者是一种独特的高危人群，需要靶向治疗来预防疾病进展。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瘤突变的影响，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 （TGFß）激活在心肌纤维化中的核心作用。在肥厚性HCM小鼠中，与安慰剂相比，给予中和抗体或血管紧张素II受体阻断剂抑制TGF-ß激活与肥厚和纤维化的发展较少相关。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。通过我们的两期CTRIP研究，我们将促进这些关键科学发现的临床转化，最终形成一项II期多中心、双盲、安慰剂对照的随机临床试验，以早期表型作为替代终点来监测治疗反应，评估强效ARB坎地沙坦在减缓疾病进展方面的安全性和有效性。通过这些努力，我们将开始重塑治疗成人发病遗传疾病的临床模式，基于早期诊断、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.