世界生命科學(xué)前沿動(dòng)態(tài)周報(bào)（八十六）

iPSCs用于界定治療心臟疾病的療法

     2013年1月11日：研究者通過(guò)使用來(lái)自一名長(zhǎng)QT綜合征 （LQTS）患者的誘導(dǎo)多能干細(xì)胞（iPSCs）來(lái)決定治療威脅患者生命的心律失常的過(guò)程。該研究成果發(fā)表在《普通生理學(xué)雜志》(The Journal of General Physiology)上，將引起LQTS、其他通道疾病和鐵離子通道功能障礙性疾病的治療方法的改善。

     iPSCs是被基因重組后具有胚胎干細(xì)胞功能的成體細(xì)胞，為研究疾病和開(kāi)發(fā)定制藥物療法提供了一種有價(jià)值的手段。哥倫比亞大學(xué)醫(yī)學(xué)中心的研究者在一位LQTS四歲患者身上，通過(guò)使用iPSCs分化成心肌細(xì)胞(iPSCs-CMs)，對(duì)心律失常的生理學(xué)基礎(chǔ)進(jìn)行了研究。LQTS是由任一個(gè)編碼心肌鐵離子通道或其相關(guān)蛋白的基因發(fā)生突變引起的，其可引起心律失常的發(fā)生，而后者又將導(dǎo)致痙攣和突然死亡的發(fā)生。

     在該研究中，該患者負(fù)責(zé)編碼鈉離子通道的SCN5A基因發(fā)生了突變，并且編碼磷離子通道的KCNH2基因上存在一種常見(jiàn)的多態(tài)性。

     通過(guò)對(duì)來(lái)自患者及其雙親的iPSCs-CMs進(jìn)行高壓鉗位分析，研究者認(rèn)為患者的心律失常是由SCN5A突變引起的。他們還進(jìn)一步對(duì)iPSCs-CMs進(jìn)行了體外實(shí)驗(yàn)，以確定糾正這一與鐵離子通道缺陷相關(guān)的異?；顒?dòng)的最佳療法。該研究結(jié)果顯示使用體外iPSCs技術(shù)研制個(gè)體化藥物療法治療LQTS和其他通道疾病具有光明前景。

點(diǎn)評(píng):用患者自身體細(xì)胞通過(guò)基因改造的方法獲得的iPSCs本身不是順應(yīng)生命屬性的，獲得的細(xì)胞非天然的干細(xì)胞，其產(chǎn)生的細(xì)胞與患者自身細(xì)胞沒(méi)有可比性，試圖通過(guò)這種方式研究疾病并研制的藥物及療法也無(wú)法應(yīng)用于人體內(nèi)。

相關(guān)文獻(xiàn)：
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