iPSCs用于界定医治心脏疾病的疗法

     2013年1月11日：钻研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）来决定医治威胁患者性命的心律变态的过程。该钻研成就颁发在《通常生理学杂志》(The Journal of General Physiology)上，将引起LQTS、其他通路疾病和铁离子通路职能阻碍性疾病的医治步骤的改善。

     iPSCs是被基因重组后拥有胚胎干细胞职能的成体细胞，为钻研疾病和开发定造药物疗法提供了一种有价值的伎俩。哥伦比亚大学医学中心的钻研者在一位LQTS四岁患者身上，通过使用iPSCs分化有意肌细胞(iPSCs-CMs)，对心律变态的生理学基础进行了钻研。LQTS是由任一个编码心肌铁离子通路或其有关蛋白的基因发生突变引起的，其可引起心律变态的发生，而后者又将导致痉挛和忽然殒命的发生。

     在该钻研中，该患者掌管编码钠离子通路的SCN5A基因发生了突变，并且编码磷离子通路的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，钻研者以为患者的心律变态是由SCN5A突变引起的。他们还进一步对iPSCs-CMs进行了体表尝试，以确定纠正这一与铁离子通路缺点有关的异；疃淖罴蚜品。该钻研了局显示使用体表iPSCs技术研造个别化药物疗法医治LQTS和其他通路疾病拥有光明远景。

点评:用患者自身段细胞通过基因刷新的步骤获得的iPSCs自身不是适应性命属性的，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，试图通过这种方式钻研疾病并研造的药物及疗法也无法利用于人体内。

有关文件：
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