世界生命科学前沿动态周报（八十六）

iPSCs用于界定治疗心脏疾病的疗法

     2013年1月11日：研究者通过使用来自一名长QT综合征 （LQTS）患者的诱导多能干细胞（iPSCs）来决定治疗威胁患者生命的心律失常的过程。该研究成果发表在《普通生理学杂志》(The Journal of General Physiology)上，将引起LQTS、其他通道疾病和铁离子通道功能障碍性疾病的治疗方法的改善。

     iPSCs是被基因重组后具有胚胎干细胞功能的成体细胞，为研究疾病和开发定制药物疗法提供了一种有价值的手段。哥伦比亚大学医学中心的研究者在一位LQTS四岁患者身上，通过使用iPSCs分化成心肌细胞(iPSCs-CMs)，对心律失常的生理学基础进行了研究。LQTS是由任一个编码心肌铁离子通道或其相关蛋白的基因发生突变引起的，其可引起心律失常的发生，而后者又将导致痉挛和突然死亡的发生。

     在该研究中，该患者负责编码钠离子通道的SCN5A基因发生了突变，并且编码磷离子通道的KCNH2基因上存在一种常见的多态性。

     通过对来自患者及其双亲的iPSCs-CMs进行高压钳位分析，研究者认为患者的心律失常是由SCN5A突变引起的。他们还进一步对iPSCs-CMs进行了体外实验，以确定纠正这一与铁离子通道缺陷相关的异常活动的最佳疗法。该研究结果显示使用体外iPSCs技术研制个体化药物疗法治疗LQTS和其他通道疾病具有光明前景。

点评:用患者自身体细胞通过基因改造的方法获得的iPSCs本身不是顺应生命属性的，获得的细胞非天然的干细胞，其产生的细胞与患者自身细胞没有可比性，试图通过这种方式研究疾病并研制的药物及疗法也无法应用于人体内。

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Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

Cecile Terrenoire1, Kai Wang1, Kelvin W. Chan Tung4, Wendy K. Chung2,3, Robert H. Pass6, Jonathan T. Lu2, Jyh-Chang Jean5, Amel Omari5, Kevin J. Sampson1, Darrell N. Kotton5, Gordon Keller4, and Robert S. Kass1

1Department of Pharmacology, 2Department of Medicine, and 3Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032
4McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada
5Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118
6Department of Pediatrics, Albert Einstein College of Medicine, The Children’s Hospital at Montefiore, Bronx, NY 10467
Correspondence to Robert S. Kass: rsk20@columbia.edu
Abstract
Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na+ channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na+ channel current (INaL) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of INaL such that increasing the pacing rate markedly reduces INaL and, in addition, increases its inhibition by the Na+ channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband’s iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens. http://jgp.rupress.org/content/141/1/61