诱导多能干细胞技术在药物研发领域中的前景

doi:10.13523/j.cb.20171116

中国生物工程杂志

2017, Vol. 37

Issue (11): 116-122 DOI: 10.13523/j.cb.20171116

综述

诱导多能干细胞技术在药物研发领域中的前景

吴升星¹, 李艳³, 张海燕¹, 刘洋¹, 赖琼¹, 杨明^1,2

1. 江西中医药大学现代中药制剂教育部重点实验室南昌 330004;
2. 成都中医药大学成都 610075;
3. 江西中医药大学中药固体制剂制造技术国家工程研究中心南昌 330004

The Prospect of Induction of Pluripotent Stem Cell Technology in Drug Research and Development

WU Sheng-xing¹, LI Yan³, ZHANG Hai-yan¹, LIU Yang¹, LAI Qiong¹, YANG Ming^1,2

1. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of TCM, Nanchang 330004, China;
2. Chengdu University of TCM, Chengdu 610075, China;
3. National Engineering Research Center for Traditional Chinese Medicine Solid Chemicals Manufacturing, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China

全文: PDF(683 KB) HTML

摘要： 由于基础研究环境和临床环境之间存在的转化差异，使得药物在临床阶段取得成功仍然具有挑战性。诱导多能干（iPS）细胞的诞生为药物研发领域带来了新的希望，使研究者能在体外人性化各种药理学和毒理学模型。人iPS衍生细胞的可获得性，特别是可以定向分化成特定的功能性细胞、组织和器官，一方面为疾病机制研究与细胞治疗提供了全新的途径。另一方面，转化研究中的生物标记物提供了评估临床前基础研究环境和临床环境下毒理学及药理学影响的可衡量的指标，而iPS细胞给生物标记物的研究带来了全新的思路。从转化研究的角度概述了基于iPS细胞药物发现的现行策略，阐明了iPS细胞的潜力以及生物标志物在药物发现和发展整个过程中的作用，突出在该领域有待改进的地方，以期为进一步相关性研究提供一定参考，为新药研发提供新的思路与方法。

关键词： iPS细胞; 生物标记物; 药物研发; 临床前研究

Abstract: Despite continuous efforts to improve the process of drug discovery and development,achieving success at the clinical stageremains challenging because of a persistent translational gap between the preclinical and clinical settings. Under these circumstances, the discovery of human induced pluripotent stem (iPS) cells has brought new hope to the drug discovery field because they enable scientists to humanize a variety of pharmacological and toxicological models in vitro.Theavailability of human iPS cell-derived cells,their potential to differentiate into specific functional cells, tissues and organs, has provided new avenues for studying diseases and cell therapy. Biomarkers are an essential part of the translational effort to shift new discoveries from bench to bedside as they provide a measurable indicator to evaluate pharmacological and toxicological effects in both preclinical and clinical settings. In general, during the preclinical stage of drug development, in vitro models that are established to recapitulate human diseases are validated by using a set of biomarkers; however, their translatability to a clinical setting remains problematic. An overview of the current strategies for human iPS cell-based drug discovery from the perspective of translational research is provided.

Key words: Biomarker Preclinical study iPS cells Drug discovery

收稿日期: 2017-05-17 出版日期: 2017-11-15

ZTFLH:

Q813

基金资助: 江西省科技专项（20123BBG70201）、江西省重大科技专项（2010AZD00303）资助项目

通讯作者: 李艳, 张海燕 E-mail: liyan_62@163.com;haiyansl@163.com

	服务
	把本文推荐给朋友
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	吴升星
	赖琼
	张海燕
	刘洋
	杨明
	李艳

引用本文:

吴升星, 李艳, 张海燕, 刘洋, 赖琼, 杨明. 诱导多能干细胞技术在药物研发领域中的前景[J]. 中国生物工程杂志, 2017, 37(11): 116-122.

WU Sheng-xing, LI Yan, ZHANG Hai-yan, LIU Yang, LAI Qiong, YANG Ming. The Prospect of Induction of Pluripotent Stem Cell Technology in Drug Research and Development. China Biotechnology, 2017, 37(11): 116-122.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.20171116 或 https://manu60.magtech.com.cn/biotech/CN/Y2017/V37/I11/116

[1]	Caulfield T, Sipp D, Murry C E, et al. SCIENTIFIC COMMUNITY. Confronting stem cell hype. Science, 2016, 352(6287):776.
[2]	Avior Y, Sagi I, Benvenisty N. Pluripotent stem cells in disease modelling and drug discovery. Nature Reviews Molecular Cell Biology, 2016, 17(3):170.
[3]	Wu Y, Li O, He C, et al. Generation and characterization of induced pluripotent stem cells from guinea pig fetal fibroblasts. Molecular Medicine Reports, 2017, 15(6):3690-3698.
[4]	Spitalieri P, Talarico V, Luchetti A, et al. Generation of disease-specific induced pluripotent stem cells from human fetal extra-embryonic tissues. Cytotherapy, 2014, 16(4):S9-S9.
[5]	Singh A M, Perry D W, Steffey V V A, et al. Decoding the epigenetic heterogeneity of human pluripotent stem cells with seamless gene editing. Methods in Molecular Biology, 2016, 1516:153.
[6]	Faulknerjones A, Fyfe C, Cornelissen D J, et al. Bioprinting of human pluripotent stem cells and their directed differentiation into hepatocyte-like cells for the generation of mini-livers in 3D. Biofabrication, 2015, 7(4):044102.
[7]	Smietana K, Siatkowski M, Møller M. Trends in clinical success rates. Nature Reviews Drug Discovery, 2016, 15(6):379.
[8]	De V J, Bouckenheimer J, Sansac C, et al. Human induced pluripotent stem cells:A disruptive innovation. Current Research in Translational Medicine, 2016, 64(2):91-96.
[9]	Mullane K, Winquist R J, Williams M. Translational paradigms in pharmacology and drug discovery. Biochemical Pharmacology, 2014, 87(1):189-210.
[10]	Zhao X, Modur V, Carayannopoulos L N, et al. Biomarkers in pharmaceutical research. Clinical Chemistry, 2015, 61(11):1343-1353.
[11]	Quintana-Bustamante O, Segovia J C. Generation of patient-specific induced pluripotent stem cell from peripheral blood mononuclear cells by sendai reprogramming vectors. Methods in Molecular Biology, 2016, 1353:1-11.
[12]	Spitalieri P, Talarico V, Luchetti A, et al. Generation of disease-specific induced pluripotent stem cells from human fetal extra-embryonic tissues. Cytotherapy, 2014, 16(4):S9-S9.
[13]	Narayanan G, Sheila M, Chai J, et al. Generation of sibling-matched induced pluripotent stem cell lines from spinal and bulbar muscular atrophy patients. Stem Cell Research, 2017, 20:30-33.
[14]	Slaugenhaupt S A, Gusella J F. Methods for Altering mRNA Splicing and Treating Familial Dysautonomia by Administering Benzyladenine:US,9265766 B2. 2016-02-23.
[15]	Inoue H, Nagata N, Kurokawa H, et al. iPS cells:a game changer for future medicine. Embo Journal, 2014, 33(5):409.
[16]	Zhang Z N, Freitas B C, Qian H, et al. Layered hydrogels accelerate iPSC-derived neuronal maturation and reveal migration defects caused by MeCP2 dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(12):3185.
[17]	Tang X, Kim J, Zhou L, et al. KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.. Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(3):751.
[18]	Tanaka T, Takahashi K, Yamane M, et al. Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery. Blood, 2012, 120(6):1299.
[19]	Liu G H, Suzuki K, Qu J, et al. Targeted gene correction of laminopathy-associated LMNA mutations in patient-specific iPSCs. Cell Stem Cell, 2011, 8(6):688-694.
[20]	Bannon D, Landau A M, Doudet D J. How relevant are imaging findings in animal models of movement disorders to human disease? Current Neurology & Neuroscience Reports, 2015, 15(8):53.
[21]	Suarez C D, Littlepage L E. Patient-derived tumor xenograft models of breast cancer. Methods MolBiol, 2016, 1406:211-223.
[22]	Rinaldi F, Perlingeiro R C. Stem cells for skeletal muscle regeneration:therapeutic potential and roadblocks. Translational Research, 2014, 163(4):409-417.
[23]	Cevatemre B, Ulukaya E, Sarimahmut M, et al. The M30 assay does not detect apoptosis in epithelial-derived cancer cells expressing low levels of cytokeratin 18. Tumor Biology, 2015, 36(9):6857-6865.
[24]	Öngen Z. What do biomarkers mark? Anatolian Journal of Cardiology, 2016, 16(2):75.
[25]	Ding Y, Qin Z H, Cun-Shuan X U. Generation of hepatocyte-like cells from induced pluripotent stem cells. Chinese Journal of Biochemistry & Molecular Biology, 2016,32(1):41-48.
[26]	Swinney D C, Anthony J. How Were New Medicines Discovered? Nature Reviews Drug Discovery, 2011, 10(7):507-519.
[27]	Lee H, Lee J W. Target identification for biologically active small molecules using chemical biology approaches. Archives of Pharmacal Research, 2016, 39(9):1-9.
[28]	Wagner B, Schreiber S. The power of sophisticated phenotypic screening and modern mechanism-of-action methods. Cell Chemical Biology, 2016, 23(1):3-9.
[29]	Kobari L, Yates F, Oudrhiri N, et al. Human induced pluripotent stem cells can reach complete terminal maturation:in vivo and in vitro evidence in the erythropoietic differentiation model. Haematologica, 2012, 97(12):1795-803.
[30]	Janzen W P. Screening technologies for small molecule discovery:The State of the Art. Chemistry & Biology, 2014, 21(9):1162-1170.
[31]	Tang S, Xie M, Cao N, et al. Patient-specific induced pluripotent stem cells for disease modeling and phenotypic drug discovery. Journal of Medicinal Chemistry, 2016, 59(1):2.
[32]	Lee W M. Drug-induced hepatotoxicity. New England Journal of Medicine, 2010, 7(5):477-485.
[33]	Chen M, Suzuki A, Borlak J, et al. Drug-induced liver injury:interactions between drug properties and host factors. Journal of Hepatology, 2015, 63(2):503-514.
[34]	Tasnim F, Toh Y C, Qu Y, et al. Functionally enhanced human stem cell derived hepatocytes in galactosylated cellulosic sponges for hepatotoxicity testing. Molecular Pharmaceutics, 2016, 13(6):1947.
[35]	Zhu S, Rezvani M, Harbell J, et al. Mouse liver repopulation with hepatocytes generated from human fibroblasts. Nature, 2014, 508(7494):93.
[36]	Hay M, Thomas D W, Craighead J L, et al. Clinical development success rates for investigational drugs. Nature Biotechnology, 2014, 32(1):40.
[37]	Vernetti L A, Senutovitch N, Boltz R, et al. A human liver microphysiology platform for investigating physiology, drug safety, and disease models. Experimental Biology & Medicine, 2016, 241(1):101.
[38]	Schwartz M P, Hou Z, Propson N E, et al. Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(40):12516.
[39]	Yu Y, Sun S, Wang S, et al. Liensinine-and neferine-induced cardiotoxicity in primary neonatal rat cardiomyocytes and human-induced pluripotent stem cell-derived cardiomyocytes. International Journal of Molecular Sciences, 2016, 17(2):186.
[40]	Wei D, Mak R H. Early markers of obesity-related renal injury in childhood. Pediatric Nephrology, 2015, 30(1):1-4.
[41]	Tiong H Y, Huang P, Xiong S, et al. Drug-induced nephrotoxicity:clinical impact and pre-clinical in vitro models. Molecular Pharmaceutics, 2014, 11(7):1933-1948.
[42]	Van M L, Moerland M, Cohen A F, et al. Urinary kidney biomarkers for early detection of nephrotoxicity in clinical drug development. British Journal of Clinical Pharmacology, 2014, 77(6):947-957.
[43]	Snoeck H W. Modeling human lung development and disease using pluripotent stem cells. Development, 2015, 142(1):13-16.
[44]	Tukker A M, de Groot M W, Wijnolts F M, et al. Is the time right for in vitro neurotoxicity testing using human iPSC-derived neurons? Altex, 2016, 33(3):261.
[45]	Hartmann N B, Ågerstrand M, Lützhøft H C H, et al. NanoCRED:A transparent framework to assess the regulatory adequacy of ecotoxicity data for nanomaterials-relevance and reliability revisited. Nanoimpact, 2017,6:81-89.
[46]	Aday S, Cecchelli R, Halliervanuxeem D, et al. Stem cell-based human blood-brain barrier models for drug discovery and delivery. Trends in Biotechnology, 2016, 34(5):382-393.
[47]	Wheeler H E, Wing C, Delaney S M, et al. Modeling chemotherapeutic neurotoxicity with human induced pluripotent stem cell-derived neuronal cells. PLoS One, 2015, 10(2):e0118020.
[48]	Sayed N, Liu C, Wu J C. Translation of human-induced pluripotent stem cells:from clinical trial in a dish to precision medicine. Journal of the American College of Cardiology, 2016, 67(18):2161-2176.

[1]	武瑞君,李治非,张鑫,濮润,敖翼,孙燕荣. 新冠病毒抗体药物研发进展及展望分析[J]. 中国生物工程杂志, 2020, 40(5): 1-6.
[2]	朱小丽,黄翠,马丽丽,张超,巩玥,赵婉雨,赵秀芳,郭文姣,彭皓,张吉,梁慧刚. 新型冠状病毒病(COVID-19)研究进展[J]. 中国生物工程杂志, 2020, 40(1-2): 38-50.
[3]	李振虎,武云飞,潘莹,任兆翔,古向超,唐亮,王辛中,张娟. 肿瘤免疫治疗新药研发及生物标记物研究[J]. 中国生物工程杂志, 2019, 39(2): 38-48.
[4]	蒋析文,董子维,刘悦,朱小亚. 生物标记物与精准医疗研究进展[J]. 中国生物工程杂志, 2019, 39(2): 74-81.
[5]	谢志勇,周翔. 基于机器学习的医学影像分析在药物研发和精准医疗方面的应用[J]. 中国生物工程杂志, 2019, 39(2): 90-100.
[6]	Rachael Ritchie, Marie-Ange Baucher. 在医疗保健领域开发和使用生物标记物的政策性问题[J]. 中国生物工程杂志, 2014, 34(1): 101-126.
[7]	孙昊, 卢存福, 郭允倩. LSD1通过和Oct4/Nanog相互作用调节诱导多能干细胞的形成[J]. 中国生物工程杂志, 2012, 32(12): 25-29.
[8]	单威, 余勤, 刘丽珍, 王标. 诱导性多能干细胞向神经细胞分化的研究进展[J]. 中国生物工程杂志, 2012, 32(09): 82-86.
[9]	马海滨, 侯玲玲, 王晓宇, 关伟军, 马月辉. 诱导性多潜能干细胞(iPS细胞)的研究进展[J]. 中国生物工程杂志, 2011, 31(8): 124-132.
[10]	付蒙, 张艳梅, 王佃亮, 曾虹燕, 孙晋伟. 人羊膜间充质干细胞的生物学特性及临床前研究[J]. 中国生物工程杂志, 2011, 31(12): 115-119.
[11]	丁锡申. 基因工程药物的过去、现在和将来[J]. 中国生物工程杂志, 1998, 18(3): 2-6.
[12]	丁锡申. 我国基因工程药物产业化进程中存在的问题[J]. 中国生物工程杂志, 1996, 16(3): 4-5.
[13]	丁锡申. 基因工程药物的审批[J]. 中国生物工程杂志, 1995, 15(5): 5-7.
[14]	丁锡申. 基因工程药物在国内的开发情况[J]. 中国生物工程杂志, 1995, 15(4): 46-47.

Viewed

Full text

Abstract

Cited

Shared

Discussed