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天下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）患者的诱导多醒目细胞（iPSCs）来决议治疗威胁患者生命的心律失常的历程。该研究效果揭晓在《通俗心理学杂志》(The Journal of General Physiology)上，将引起LQTS、其他通道疾病和铁离子通道功效障碍性疾病的治疗要领的改善。
iPSCs是被基因重组后具有胚胎干细胞功效的成体细胞，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分解故意肌细胞(iPSCs-CMs)，对心律失常的心理学基础举行了研究。LQTS是由任一个编码心肌铁离子通道或其相关卵白的基因爆发突变引起的，其可引起心律失常的爆发，此后者又将导致痉挛和突然殒命的爆发。
在该研究中，该患者认真编码钠离子通道的SCN5A基因爆发了突变，并且编码磷离子通道的KCNH2基因上保存一种常见的多态性。
通过对来自患者及其双亲的iPSCs-CMs举行高压钳位剖析，研究者以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举行了体外实验，以确定纠正这一与铁离子通道缺陷相关的异� Ｔ硕淖罴蚜品�。该研究效果显示使用体外iPSCs手艺研制个体化药物疗法治疗LQTS和其他通道疾病具有灼烁远景。
点评:用患者自身体细胞通过基因刷新的要领获得的iPSCs自己不是顺应生命属性的，获得的细胞非自然的干细胞，其爆发的细胞与患者自身细胞没有可比性，试图通过这种方法研究疾病并研制的药物及疗法也无法应用于人体内。
相关文献：
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