Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies.
Hypertrophic cardiomyopathy: Mutations to mechanisms to therapies.
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DOI：
10.3389/fphys.2022.975076
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发表时间：
2022
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
肥厚型心肌病（HCM）影响超过1/500的人在一般人群中的广泛负担的发病率的形式心律失常，心力衰竭和猝死。自从发现HCM的遗传基础以来，该领域已经揭示了这些基因突变的主要影响的重要见解，特别是对于肌球蛋白重链基因，这是最常见的突变基因之一。在过去的10年里，我们的小组使用最先进的生物化学和生物物理工具，结合临床遗传学和心肌肌球蛋白结构分析的见解，研究了HCM突变对人β-心肌肌球蛋白重链的分子效应。首要的假设是，HCM引起的肌节蛋白突变导致肌节水平的过度收缩，我们已经表明，与肌动蛋白相互作用的肌球蛋白分子数量的增加是一个主要的驱动因素。最近，两个制药公司已经开发了小分子抑制剂的人心肌肌球蛋白，以抵消HCM发病机制的分子后果。其中一种抑制剂（mavacamten）最近在HCM患者中完成了成功的III期试验后获得了FDA的批准，另一种（aficamten）目前正在III期试验中进行评估。肌球蛋白抑制剂将是用于治疗HCM的第一类药物，其具有强有力的临床试验证据的疗效，并且靶向HCM发病机制的基本机制。肌球蛋白抑制剂在HCM中的成功为寻找直接靶向肌节的其他新药打开了大门，因为我们对这种疾病的遗传学和基本机制有了更多的了解。
Hypertrophic cardiomyopathy (HCM) affects more than 1 in 500 people in the general population with an extensive burden of morbidity in the form of arrhythmia, heart failure, and sudden death. More than 25 years since the discovery of the genetic underpinnings of HCM, the field has unveiled significant insights into the primary effects of these genetic mutations, especially for the myosin heavy chain gene, which is one of the most commonly mutated genes. Our group has studied the molecular effects of HCM mutations on human β-cardiac myosin heavy chain using state-of-the-art biochemical and biophysical tools for the past 10 years, combining insights from clinical genetics and structural analyses of cardiac myosin. The overarching hypothesis is that HCM-causing mutations in sarcomere proteins cause hypercontractility at the sarcomere level, and we have shown that an increase in the number of myosin molecules available for interaction with actin is a primary driver. Recently, two pharmaceutical companies have developed small molecule inhibitors of human cardiac myosin to counteract the molecular consequences of HCM pathogenesis. One of these inhibitors (mavacamten) has recently been approved by the FDA after completing a successful phase III trial in HCM patients, and the other (aficamten) is currently being evaluated in a phase III trial. Myosin inhibitors will be the first class of medication used to treat HCM that has both robust clinical trial evidence of efficacy and that targets the fundamental mechanism of HCM pathogenesis. The success of myosin inhibitors in HCM opens the door to finding other new drugs that target the sarcomere directly, as we learn more about the genetics and fundamental mechanisms of this disease.
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DOI：
10.1073/pnas.1809540115
发表时间：
2018-08-28
影响因子：
11.1
作者：
Anderson, Robert L.;Trivedi, Darshan V.;Spudich, James A.
通讯作者：
Spudich, James A.
DOI：
10.1073/pnas.0606741103
发表时间：
2006-11-21
影响因子：
11.1
作者：
Blankenfeldt, Wulf;Thoma, Nicolas H.;Schlichting, Ilme
通讯作者：
Schlichting, Ilme
影响因子：
8.8
作者：
Adhikari, Arjun S.;Kooiker, Kristina B.;Ruppel, Kathleen M.
通讯作者：
Ruppel, Kathleen M.
DOI：
10.1196/annals.1341.008
发表时间：
2005-01-01
期刊：
COMMUNICATIVE CARDIAC CELL
影响因子：
--
作者：
Bers, DM;Guo, T
通讯作者：
Guo, T
影响因子：
64.5
作者：
Davis J;Davis LC;Correll RN;Makarewich CA;Schwanekamp JA;Moussavi-Harami F;Wang D;York AJ;Wu H;Houser SR;Seidman CE;Seidman JG;Regnier M;Metzger JM;Wu JC;Molkentin JD
通讯作者：
Molkentin JD