Please wait a minute...

中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2020, Vol. 40 Issue (11): 73-81    DOI: 10.13523/j.cb.2006040
    
Application of Gene Technology in the Treatment of Type 2 Diabetes Mellitus
CHEN Qing-yu,WANG Xian-zhong,ZHANG Jiao-jiao()
College of Veterinary Medicine, Southwest University, Chongqing 400715, China
Download: HTML   PDF(475KB) HTML
Export: BibTeX | EndNote (RIS)      

Abstract  

Type 2 diabetes mellitus (T2DM) is a kind of chronic metabolic disease caused by β-cell damage and insulin tolerance. The rapid growth of its morbidity and high mortality caused by complications has become a medical problem. At present, T2DM is mainly treated with hypoglycemic drugs and insulin sensitizers, but these drugs will have serious side effects. And these drugs can’t control blood glucose and prevent various chronic complications for a long time. Therefore, gene therapy is the main direction of future medical development. Gene therapy can not only target to regulate blood glucose level and improve the effect of lowering blood glucose, but also reduce the complications caused by abnormal glucose metabolism and protect tissues and organs from damage. Based on the understanding of traditional medicine in the treatment of diabetes, the effect and advantages of gene technology in the treatment of T2DM are reviewed, which is not only conducive to the prevention and individualized treatment of T2DM, but also provides a new treatment for diabetic complications.

Key words： T2DM      Drug therapy      Gene therapy      Viral vectors      CRISPR     
Received: 23 June 2020      Published: 11 December 2020
ZTFLH:  Q78  
Corresponding Authors: Jiao-jiao ZHANG     E-mail: zhangjjff@126.com
Service
E-mail this article
Add to my bookshelf
Add to citation manager
E-mail Alert
RSS
Articles by authors
Qing-yu CHEN
Xian-zhong WANG
Jiao-jiao ZHANG
Cite this article:

CHEN Qing-yu,WANG Xian-zhong,ZHANG Jiao-jiao. Application of Gene Technology in the Treatment of Type 2 Diabetes Mellitus. China Biotechnology, 2020, 40(11): 73-81.

URL:

https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2006040     OR     https://manu60.magtech.com.cn/biotech/Y2020/V40/I11/73

类别 常用药物 适应证 用药方式 作用机制 优缺点
胰岛素及胰岛素类似物 诺和锐、诺和灵N、诺和平 T1DM、治疗效果不佳的T2DM 皮下注射、
口服		 与受体结合后促进葡萄糖的摄取和利用,并抑制糖原分解和异生 优点:用于日常基础控制血糖
缺点:治疗过程中需进行血糖监测避免不良反应
双胍类 盐酸二甲双胍 单纯饮食控制不满意的T2DM 口服 减少肝脏葡萄糖的输出,恢复胰岛素对腺苷环化酶的抑制,促进糖无氧酵解;改善外周胰岛素抵抗,抑制肠道对葡萄糖的吸收和肝糖输出;改善胰岛素敏感性而降低血糖 优点:可全程联合其他药物进行治疗,治疗首选药
缺点:会有胃肠道反应,需先从小剂量开始用药,形成耐受;长期使用者应注意维生素B12缺乏的可能性
磺脲类促泌药 格列喹酮、格列美脲 非肥胖
T2DM患者		 口服 作用于胰岛β细胞的K+-ATP通道,使K+外流受限,Ca2+内流刺激胰岛素释放,增加体内胰岛素水平进而降低血糖;直接刺激胰岛β细胞分泌胰岛素 优点:可作口服降糖药,对患者而言更加方便,与糖尿病微血管病变和大血管病变发生的风险下降有关
缺点:使用不当会导致低血糖,尤其是在老年患者和肝、肾功能不全者,会导致体重增加
非磺脲类促泌药 瑞格列奈、那格列奈 T2DM 口服 直接刺激胰岛β细胞分泌胰岛素;刺激胰岛素早时相分泌,降低餐后血糖水平,保护胰岛细胞 优点:导致低血糖的风险,但程度较磺脲类药物轻;肾功能不全的患者可使用
缺点:会导致低血糖和体重增加
α-葡糖苷酶抑制药 阿卡波糖 以碳水化合物为主食的糖尿病患者 口服 竞争性与小肠刷状缘α-葡糖苷酶结合,抑制α-葡糖苷酶活性;延缓肠道对葡萄糖的吸收 优点:使用剂量比达到同等疗效的二甲双胍少;单独服用不会发生低血糖
缺点:胃肠道反应
TZD 曲格列酮、罗格列酮、吡格列酮、环格列酮 T2DM 口服 增加靶细胞对胰岛素作用的敏感性而降低血糖;作用于细胞核的过氧化物酶体增殖体活化受体,减少胰岛素抵抗,增加脂肪细胞、肌肉和肝中胰岛素的敏感性,提高外周组织的糖利用度,抑制肝糖原生成 优点:可使糖化血红蛋白下降0.7%~1.0%
缺点:单独使用不导致低血糖,但与胰岛素联用可增加低血糖发生的风险;该药的使用与骨折和心力衰竭风险增加有关;会导致体重增加和水肿
GLP-1受体激动药 艾塞那肽、利拉鲁肽、贝那鲁肽、利司那肽、艾塞那肽周制剂 T2DM 皮下注射 与GLP-1受体结合后,一方面刺激胰岛素分泌,另一方面减少胰高血糖素的分泌,进而降低血糖浓度 优点:显著降低三酰甘油水平、血压和体重;单独使用不明显增加低血糖发生的风险;口服降糖药治疗失败后用GLP-1有效
缺点:患者对该药物的活性成分有过敏风险
DPP-4抑制药 西格列汀、沙格列汀、维格列汀、利格列汀、阿格列汀 T2DM 口服 减少体内GLP-1的分解,增加GLP-1浓度从而促进胰岛β细胞分泌胰岛素;改善胰岛β细胞敏感性,促进胰岛素分泌;抑制胰岛α细胞分泌胰高血糖素 优点:单独使用不增加低血糖和心血管病发生的风险,肝、肾功能不全的患者可以使用
缺点:该类药物价格较高,仅有少数患者能够承担
Table 1 Drugs commonly used to treat diabetes
基因技术方法 分类 优点 缺点
病毒载体技术 慢病毒载体 基因转染效率较高,可携带较大的T2DM相关基因片段,对细胞周期没有特别要求 生物安全性较差,携带较大基因片段时病毒滴度低
腺病毒载体 病毒滴度高,转染T2DM相关基因的能力较强,不整合到宿主基因组 引起动物机体发生强烈的免疫和炎症反应
腺相关病毒载体 低致命性、低免疫原性、宿主范围广、稳定表达,适用于长期T2DM相关基因矫正,生物安全性较高 引起动物机体轻微的免疫反应
非病毒载体技术 干细胞治疗 极强的自我更新能力,多向分化为胰岛β细胞,分泌多种T2DM治疗性细胞因子 免疫排斥反应,缺血缺氧等非免疫因素
再分化 祖细胞再分化为胰岛β细胞,从根源上治疗糖尿病 再分化诱导条件未明确,再分化效率较低,去分化过程中基因组易发生突变导致细胞内致癌风险增高
CRISPR/Cas9 对T2DM相关基因高精度修饰和调控,纠正糖尿病单一致病基因 难度较高,脱靶率高,转导效率低
Table 2 The advantages and disadvantages of gene therapy for diabetes
[1]   Zhu W, Huang W, Xu Z Q, et al. Analysis of patents issued in China for antihyperglycemic therapies for type 2 diabetes mellitus. Frontiers in Pharmacology, 2019,10:586.
doi: 10.3389/fphar.2019.00586 pmid: 31214029
[2]   Zang L, Hao H, Liu J, et al. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol Metab Syndr, 2017,9:36.
[3]   Ojha A, Ojha U, Mohammed R, et al. Current perspective on the role of insulin and glucagon in the pathogenesis and treatment of type 2 diabetes mellitus. Clin Pharmacol, 2019,11:57-65.
doi: 10.2147/CPAA.S202614 pmid: 31191043
[4]   Amoah A G, Owusu S K, Schuster D P, et al. Pathogenic mechanism of type 2 diabetes in Ghanaians:the importance of beta cell secretion, insulin sensitivity and glucose effectiveness. S Afr Med J, 2002,92(5):377-384.
pmid: 12108171
[5]   Quan W, Jo E K, Lee M S. Role of pancreatic beta-cell death and inflammation in diabetes. Diabetes Obesity & Metabolism, 2013,15(Suppl 3):141-151.
[6]   Shibata S B, West M B, Du X, et al. Gene therapy for hair cell regeneration: Review and new data. Hear Res, 2020,394:107981.
doi: 10.1016/j.heares.2020.107981 pmid: 32563621
[7]   Calne R Y, Gan S U, Lee K O. Stem cell and gene therapies for diabetes mellitus. Nature Reviews Endocrinology, 2010,6(3):173-177.
doi: 10.1038/nrendo.2009.276 pmid: 20173779
[8]   Liu X, Huang H, Gao Y, et al. Visualization of gene therapy with a liver cancer-targeted adeno-associated virus 3 vector. J Cancer, 2020,11(8):2192-2200.
doi: 10.7150/jca.39579 pmid: 32127946
[9]   Modi P, Mihic M, Lewin A. The evolving role of oral insulin in the treatment of diabetes using a novel RapidMist System. Diabetes Metab Res Rev, 2002,18(Suppl 1):S38-42.
[10]   Devendra D, Liu E, Eisenbarth G S. Type 1 diabetes: recent developments. Bmj- British Medical Journal, 2004,328(7442):750-754.
doi: 10.1136/bmj.328.7442.750 pmid: 15044291
[11]   Thule P M, Liu J M. Regulated hepatic insulin gene therapy of STZ-diabetic rats. Gene Therapy, 2000,7(20):1744-1752.
[12]   Davalli A M, Galbiati F, Bertuzzi F, et al. Insulin-secreting pituitary GH3 cells: a potential beta-cell surrogate for diabetes cell therapy. Cell Transplant, 2000,9(6):841-851.
doi: 10.1177/096368970000900610 pmid: 11202570
[13]   Shaw J A, Delday M I, Hart A W, et al. Secretion of bioactive human insulin following plasmid-mediated gene transfer to non-neuroendocrine cell lines, primary cultures and rat skeletal muscle in vivo. J Endocrinol, 2002,172(3):653-672.
doi: 10.1677/joe.0.1720653 pmid: 11874714
[14]   Keckesova Z, Ylinen L M J, Towers G J, et al. Identification of a RELIK orthologue in the European hare (Lepus europaeus) reveals a minimum age of 12 million years for the lagomorph lentiviruses. Virology, 2008,384(1):7-11.
doi: 10.1016/j.virol.2008.10.045 pmid: 19070882
[15]   Parr-Brownlie L C, Bosch-Bouju C, Schoderboeck L, et al. Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms. Front Mol Neurosci, 2015,8:14.
doi: 10.3389/fnmol.2015.00014 pmid: 26041987
[16]   Sakuma T, Barry M A, Ikeda Y. Lentiviral vectors: basic to translational. Biochem J, 2012,443(3):603-618.
pmid: 22507128
[17]   Vranckx L S, Demeulemeester J, Debyser Z, et al. Towards a safer, more randomized lentiviral vector integration profile exploring artificial LEDGF Chimeras. PLoS One, 2016,11(10):e0164167.
doi: 10.1371/journal.pone.0164167 pmid: 27788138
[18]   Lawson S K, Dobrikova E Y, Shveygert M, et al. p38α mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. Molecular and Cellular Biology, 2013,33(1):127-135.
doi: 10.1128/MCB.00695-12 pmid: 23109423
[19]   Gouvarchin Ghaleh H E, Bolandian M, Dorostkar R, et al. Concise review on optimized methods in production and transduction of lentiviral vectors in order to facilitate immunotherapy and gene therapy. Biomed Pharmacother, 2020,128:110276.
doi: 10.1016/j.biopha.2020.110276 pmid: 32502836
[20]   Janecka J E, Miller W, Pringle T H, et al. Molecular and genomic data identify the closest living relative of primates. Science, 2007,318(5851):792-794.
doi: 10.1126/science.1147555 pmid: 17975064
[21]   Berkowitz R, Ilves H, Lin W Y, et al. Construction and molecular analysis of gene transfer systems derived from bovine immunodeficiency virus. J Virol, 2001,75(7):3371-3382.
doi: 10.1128/JVI.75.7.3371-3382.2001 pmid: 11238863
[22]   Salmon P, Trono D. Production and titration of lentiviral vectors. Curr Protoc Hum Genet, 2007,54:12.10.1-12.10.24.
[23]   Tran R, Myers D R, Denning G, et al. Microfluidic transduction harnesses mass transport principles to enhance gene transfer efficiency. Mol Ther, 2017,25(10):2372-2382.
doi: 10.1016/j.ymthe.2017.07.002 pmid: 28780274
[24]   Chou F C, Sytwu H K. Overexpression of thioredoxin in islets transduced by a lentiviral vector prolongs graft survival in autoimmune diabetic NOD mice. J Biomed Sci, 2009,16(1):71.
[25]   Ren B, O’Brien B A, Byrne M R, et al. Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy. Journal of Gene Medicine, 2013,15(1):28-41.
pmid: 23293075
[26]   Tasyurek H M, Altunbas H A, Balci M K, et al. Therapeutic potential of Lentivirus-mediated glucagon-like peptide-1 gene therapy for diabetes. Human Gene Therapy, 2018,29(7):802-815.
doi: 10.1089/hum.2017.180 pmid: 29409356
[27]   Lopez-Talavera J C, Garcia-Ocana A, Sipula I, et al. Hepatocyte growth factor gene therapy for pancreatic islets in diabetes: reducing the minimal islet transplant mass required in a glucocorticoid-free rat model of allogeneic portal vein islet transplantation. Endocrinology, 2004,145(2):467-474.
doi: 10.1210/en.2003-1070 pmid: 14551233
[28]   Xu R, Li H, Tse L Y, et al. Diabetes gene therapy: potential and challenges. Curr Gene Ther, 2003,3(1):65-82.
doi: 10.2174/1566523033347444 pmid: 12553537
[29]   Horwitz M S, Efrat S, Christen U, et al. Adenovirus E3 MHC inhibitory genes but not TNF/Fas apoptotic inhibitory genes expressed in beta cells prevent autoimmune diabetes. Proc Natl Acad Sci USA, 2009,106(46):19450-19454.
doi: 10.1073/pnas.0910648106 pmid: 19887639
[30]   Wei F, Wang H, Chen X, et al. Dissecting the roles of E1A and E1B in adenoviral replication and RCAd-enhanced RDAd transduction efficacy on tumor cells. Cancer Biology & Therapy, 2014,15(10):1358-1366.
doi: 10.4161/cbt.29842 pmid: 25019940
[31]   Pierce M A, Chapman H D, Post C M, et al. Adenovirus early region 3 antiapoptotic 10.4K, 14.5K, and 14.7K genes decrease the incidence of autoimmune diabetes in NOD mice. Diabetes, 2003,52(5):1119-1127.
pmid: 12716741
[32]   Blackwell J L, Li H, Gomez-Navarro J, et al. Using a tropism-modified adenoviral vector to circumvent inhibitory factors in ascites fluid. Human Gene Therapy, 2000,11(12):1657-1669.
[33]   Shimizu K, Nishinaka T, Tomita K, et al. The investigation of genes, using an improved adenovirus vector, and food for the treatment and prevention of type 2 diabetes mellitus. Yakugaku Zasshi, 2019,139(1):47-51.
doi: 10.1248/yakushi.18-00163-2 pmid: 30606928
[34]   Muhammad A K, Xiong W, Puntel M, et al. Safety profile of gutless adenovirus vectors delivered into the normal brain parenchyma: implications for a glioma phase 1 clinical trial. Hum Gene Ther Methods, 2012,23(4):271-284.
doi: 10.1089/hgtb.2012.060 pmid: 22950971
[35]   Suzuki R, Tobe K, Aoyama M, et al. Both insulin signaling defects in the liver and obesity contribute to insulin resistance and cause diabetes in Irs2(-/-) mice. Journal of Biological Chemistry, 2004,279(24):25039-25049.
[36]   Reach G. Towards a cell therapy for diabetes? An epistemiological perspective. J Soc Biol, 2001,195(1):83-90.
pmid: 11530507
[37]   Schwitzgebel V M, Scheel D W, Conners J R, et al. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas. Development, 2000,127(16):3533-3542.
pmid: 10903178
[38]   Wang D, Tai P W L, Gao G P. Adeno-associated virus vector as a platform for gene therapy delivery. Nature Reviews Drug Discovery, 2019,18(5):358-378.
doi: 10.1038/s41573-019-0012-9 pmid: 30710128
[39]   Yl?-Herttuala S. Endgame: glybera finally recommended for approval as the first gene therapy drug in the European Union. Mol Ther, 2012,20(10):1831-1832.
doi: 10.1038/mt.2012.194 pmid: 23023051
[40]   Prasad K M, Yang Z, Bleich D, et al. Adeno-associated virus vector mediated gene transfer to pancreatic beta cells. Gene Ther, 2000,7(18):1553-1561.
doi: 10.1038/sj.gt.3301279 pmid: 11021593
[41]   Goudy K, Song S, Wasserfall C, et al. Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice. Proc Natl Acad Sci USA, 2001,98(24):13913-13918.
doi: 10.1073/pnas.251532298 pmid: 11717448
[42]   Ueno N, Dube M G, Inui A, et al. Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the dark-phase feeding as revealed by central leptin gene therapy. Endocrinology, 2004,145(9):4176-4184.
pmid: 15155574
[43]   Tan S Y, Mei Wong J L, Sim Y J, et al. Type 1 and 2 diabetes mellitus: A review on current treatment approach and gene therapy as potential intervention. Diabetes Metab Syndr, 2019,13(1):364-372.
doi: 10.1016/j.dsx.2018.10.008 pmid: 30641727
[44]   Lin H Y, Tsai C C, Chen L L, et al. Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK. J Biomed Sci, 2010,17:56.
doi: 10.1186/1423-0127-17-56 pmid: 20624296
[45]   母义明, 臧丽. 干细胞:糖尿病治疗的新选择. 解放军医学杂志, 2015,40(7):515-518.
[45]   Mu Y M, Zang L. Stem cells: a new choice for diabetes therapy. Med J Chin PLA, 2015,40(7):515-518.
[46]   HESS D, Li L, Martin M, et al. Bone marrow-derived stem cells initiate pancreatic regeneratio. Nat Biotechnol, 2003,21(7):763-770.
doi: 10.1038/nbt841 pmid: 12819790
[47]   Lin P, Chen L, Yang N, et al. Evaluation of stem cell differentiation in diabetic rats transplanted with bone marrow mesenchymal stem cells. Transplant Proc, 2009,41(5):1891-1893.
doi: 10.1016/j.transproceed.2009.02.078
[48]   Si Y, Zhao Y, Hao H, et al. Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: identification of a novel role in improving insulin sensitivity. Diabetes, 2012,61(6):1616-1625.
pmid: 22618776
[49]   Liu X B, Zheng P, Wang X D, et al. A preliminary evaluation of efficacy and safety of Wharton’s jelly mesenchymal stem cell transplantation in patients with type 2 diabetes mellitus. Stem Cell Research & Therapy, 2014: 57.
[50]   Dor Y, Brown J, Martinez O I, et al. Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation. Nature, 2004,429(6987):41-46.
pmid: 15129273
[51]   Yahyapour R, Farhood B, Graily G, et al. Stem cell tracing through MR molecular imaging. Tissue Engineering and Regenerative Medicine, 2018,15(3):249-261.
[52]   Hunter C S, Stein R W. Evidence for loss in identity, de-differentiation, and trans-differentiation of islet beta-cells in type 2 diabetes. Frontiers in Genetics, 2017,8:35.
[53]   Gao R, Ustinov J, Korsgren O, et al. In vitro neogenesis of human islets reflects the plasticity of differentiated human pancreatic cells. Diabetologia, 2005,48(11):2296-2304.
[54]   Bonner-Weir S, Li W C, Ouziel-Yahalom L, et al. Beta-cell growth and regeneration: replication is only part of the story. Diabetes, 2010,59(10):2340-2348.
pmid: 20876724
[55]   Roy B, Yuan L, Lee Y, et al. Fibroblast rejuvenation by mechanical reprogramming and redifferentiation. Proc Natl Acad Sci USA, 2020,117(19):10131-10141.
doi: 10.1073/pnas.1911497117 pmid: 32350144
[56]   Kimbrel E A, Lanza R. Current status of pluripotent stem cells: moving the first therapies to the clinic. Nature Reviews Drug Discovery, 2015,14(10):681-692.
[57]   Balboa D, Prasad R B, Groop L, et al. Genome editing of human pancreatic beta cell models: problems, possibilities and outlook. Diabetologia, 2019,62(8):1329-1336.
doi: 10.1007/s00125-019-4908-z pmid: 31161346
[58]   王晗月, 杨晓菲, 胡巢凤, 等. CRISPR/Cas9基因编辑技术在糖尿病细胞治疗中的应用研究进展. 生命科学, 2019,31(7):723-730.
[58]   Wang H Y, Hu X F, Hu C F, et al. CRISPR/Cas9 gene editing in diabetes cell therapy: recent advances. Chinese Bulletin of Life Sciences, 2019,31(7):723-730.
[59]   Ma S, Viola R, Sui L, et al. beta Cell replacement after gene editing of a neonatal diabetes-causing mutation at the insulin locus. Stem Cell Reports, 2018,11(6):1407-1415.
doi: 10.1016/j.stemcr.2018.11.006 pmid: 30503261
[60]   Maxwell K G, Augsornworawat P, Velazco-Cruz L, et al. Gene-edited human stem cell-derived beta cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Science Translational Medicine, 2020,12(540):eaax9106.
[61]   Chung J Y, Ain Q U, Song Y, et al. Targeted delivery of CRISPR interference system against Fabp4 to white adipocytes ameliorates obesity, inflammation, hepatic steatosis, and insulin resistance. Genome Research, 2019,29(9):1442-1452.
pmid: 31467027
[1] WU Xiu-zhi,WANG Hong-jie,ZU Yao. Functional Study of hoxa1a Regulating Craniofacial Bone Development in Zebrafish[J]. China Biotechnology, 2021, 41(9): 20-26.
[2] ZHAO Xia,ZHU Zhe,ZU Yao. tbx2b Affects Atrioventricular Canal Development in Zebrafish[J]. China Biotechnology, 2021, 41(8): 1-7.
[3] ZHAO Xiao-yu,XU Qi-ling,ZHAO Xiao-dong,AN Yun-fei. Enhancing Lentiviral Vector Transduction Efficiency for Facilitating Gene Therapy[J]. China Biotechnology, 2021, 41(8): 52-58.
[4] BI Bo,ZHANG Yu,ZHAO Hui. Application of Yeast Hybrid System in Study of Off-target Rate of CRISPR/Cas9 Gene Editing System[J]. China Biotechnology, 2021, 41(6): 27-37.
[5] HU Xuan,WANG Song,YU Xue-ling,ZHANG Xiao-peng. Construction of a Destabilized EGFP Cell Model for Gene Editing Evaluation[J]. China Biotechnology, 2021, 41(5): 17-26.
[6] WANG Yan-mei,KOU Hang,MA Mei,SHEN Yu-yu,ZHAO Bao-ding,LU Fu-ping,LI Ming. CRISPR/Cas9-mediated Inactivation of the Pectinase Gene in Aspergillus niger and Evaluation of the Mutant Strain[J]. China Biotechnology, 2021, 41(5): 35-44.
[7] YANG Meng-bing,JIANG Yi-lin,ZHU Lei,AN Xue-li,WAN Xiang-yuan. CRISPR/Cas Plant Genome Editing Systems and Their Applications in Maize[J]. China Biotechnology, 2021, 41(12): 4-12.
[8] GUO Yang,CHEN Yan-juan,LIU Yi-chen,WANG Hai-jie,WANG Cheng-ji,WANG Jue,WAN Ying-han,ZHOU Yu,XI Jun,SHEN Ru-ling. Pd-1 Gene Knockout Mouse Model Construction and Preliminary Phenotype Verification[J]. China Biotechnology, 2021, 41(10): 1-11.
[9] GUO Yang,WAN Ying-han,WANG Jue,GONG Hui,ZHOU Yu,CI Lei,WAN Zhi-peng,SUN Rui-lin,FEI Jian,SHEN Ru-ling. Toll-like Receptor 4 (TLR4) Gene Knockout Mouse Model Construction and Preliminary Phenotypic Analysis[J]. China Biotechnology, 2020, 40(6): 1-9.
[10] FAN Bin,CHEN Huan,SONG Wan-ying,CHEN Guang,WANG Gang. Advances in Lactic Acid Bacteria Gene Modification[J]. China Biotechnology, 2020, 40(6): 84-92.
[11] HUANG Sheng, YAN Qi-tao, XIONG Shi-lin, PENG Yi-qi, ZHAO Rui. Construction of CHD5 Gene Overexpressing Lentiviral Vector Based on CRISPR/Cas9-SAM System and the Effect of CHD5 on Proliferation, Migration and Invasion in T24 Cells[J]. China Biotechnology, 2020, 40(3): 1-8.
[12] LEI Hai-ying,ZHAO Qing-song,BAI Feng-lin,SONG Hui-fang,WANG Zhi-jun. Identification of Developing-related Gene ZmCen Using CRISPR/Cas9 in Maize[J]. China Biotechnology, 2020, 40(12): 49-57.
[13] WANG Yue,MU Yan-shuang,LIU Zhong-hua. Progress of CRISPR/Cas Base Editing System[J]. China Biotechnology, 2020, 40(12): 58-66.
[14] XU Ying-yong. Current Status and Challenges of Gene Therapy Products[J]. China Biotechnology, 2020, 40(12): 95-103.
[15] WANG Wei-dong,DU Jia-ru,ZHANG Yun-shang,FAN Jian-ming. The Application of CRISPR/Cas9 in the Treatment of Human Virus Infection-Related Diseases[J]. China Biotechnology, 2020, 40(12): 18-24.
主管：中国科学院 　主办：中国科学院文献情报中心 　中国生物技术发展中心 　中国生物工程学会