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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2020, Vol. 40 Issue (12): 95-103    DOI: 10.13523/j.cb.2008120
    
Current Status and Challenges of Gene Therapy Products
XU Ying-yong()
Zai Lab (Shanghai) Co., Ltd,Shanghai 201210,China
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Abstract  

Gene therapy is an approach treating certain diseases by transferring therapeutic genetic material to target cells. Gene therapy may provide the possibility of “one-time” cure paving the way as an important treatment armamentarium in near future. However, challenges subsuming long-term efficacy and safety data, accessibility, and regulatory policy forgene therapy need to be addressed. The review will start with basic concept and history, to discuss current status and future prospects of gene therapy.

Key words： Gene therapy      Virus vector      Chimeric antigen receptor T cells     
Received: 13 August 2020      Published: 14 January 2021
ZTFLH:  Q789  
Corresponding Authors: Ying-yong XU     E-mail: yingyongxu113@163.com
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Cite this article:

XU Ying-yong. Current Status and Challenges of Gene Therapy Products. China Biotechnology, 2020, 40(12): 95-103.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2008120     OR     https://manu60.magtech.com.cn/biotech/Y2020/V40/I12/95

Fig.1 Milestones in gene therapy history
年份 品名,药物 给药 载体 获批 适应证 注册临床研究 定价(地区)( ① 数据来源:https://www.evaluate.com/
)
2003 Gendicine, (Ad5RSV-p53) 瘤内 Ad NMPA 头颈部鳞癌 II期研究
(N=135)		 3 380元人民币
一次(中国)
2012 Glybera
(Alipogene tiparvovec)		 肌内 AAV1 EMA 脂蛋白脂酶缺乏 单臂研究
(N=27)		 约122万美元
(德国)
2015 Imlygic(Talimogene
laherparepvec)		 瘤内 HSV FDA/EMA 黑色素瘤 三期研究
(N=436)		 平均5.4万美元/
年(美国)
2016 Strimvelis (CD34+细胞
ADA cDNA)		 静脉 RV EMA ADA-SCID 单臂研究
(N=18)		 59.4万欧元
(仅在意大利使用)
2017 Kymriah (Tisagenlecleucel) 静脉 LV FDA B-ALL 单臂研究
(N=75)		 47.5万美元(美国)
Yescarta (Axicabtagene
ciloleucel)		 静脉 RV FDA B-NHL 单臂研究
(N=111)		 37.3万美元(美国)
Luxturna (Voretigene
neparvovec-rzyl)		 视网膜下 AAV2 FDA RPE65-相关
视网膜营养不良		 三期研究
(N=29)		 85万美元,基于疗效
的退款计划(美国)
2019 Zynteglo (LentiGlobin) 静脉 LV EMA β-地中海贫血 单臂研究
(N=22)		 177万美元,
5年分期
Zolgensma
(Onasemnogene)		 静脉 AAV9 FDA SMA 单臂研究
(N=15+21)		 212.5万美元,
5年分期(美国)
2020 Tecartus (Brexucabtagene
autoeucel)		 静脉 RV FDA MCL 单臂研究
(N=60)		 未知
Table 1 Summary of selected approved gene therapy products
产品 公司 适应证 载体-核酸 目前状态
LentiGlobin Bluebird Bio 地中海贫血/镰刀状贫血 LV-β-球蛋白 已批准
AAVrh74.MHCK7. Micro-Dystrophin Sarepta Therapeutics 杜氏肌营养不良 微小肌营养不良蛋白基因 临床II期
SGT-001 Solid Bioscience 杜氏肌营养不良 微小肌营养不良蛋白基因 临床II期
Zolgensma Novartis 脊髓性肌萎缩 AAV9-SMN 已批准
Valoctocogene roxaparvovec Biomarin Pharmaceutical 血友病A AAV5-FVIII BLA阶段
AMT-061 UniQure 血友病B AAV5-FIX-Padua 临床III期
SPK-8011 Spark Therapeutics 血友病A AAV-FVIII 临床II期
Ad-RTS-Hil-12 Ziopharm Oncology 恶性胶质瘤 Ad-IL-12 临床II期
HMI-102 Homology Medicines 苯丙酮尿症 AAVHSCs-PAH 临床前
NSR-REP1 Nightstar Therapeutics 无脉络膜症 AAV-REP1 临床III期
Table 2 The projection of key gene therapy products to year 2024
名称 优势 劣势 临床应用举例
腺病毒 可携带相对大的基因片段 相对复杂的病毒基因组,可在靶细胞中复制,具有免疫原性 如Gendicine
AAV 小病毒,免疫反应弱,基因转移效率高。不整合入宿主DNA中,适用于非分裂细胞 携带相对小的基因片段 应用场景广泛,是目前最常用的病毒载体,如血友病、SMA等[24]
疱疹病毒 可携带相对大的基因片段 相对复杂的病毒基因组,对细胞有潜在细胞毒作用 如Imlygic,治疗黑色素瘤
慢病毒 可稳定整合入基因组或非分裂细胞中,基因表达时间长,免疫原性弱 插入突变风险,体内递送效率低 如LentiGlobin,治疗地中海贫血;Kymriah治疗B-ALL
逆转录病毒 可稳定整合入基因组中,基因表达时间长,免疫原性弱 仅整合进分裂细胞中,存在插入突变风险,体内递送效率低 如Yescarta,治疗B-淋巴瘤
Table 3 Virus vectors used in gene therapy products
时间 主体 法规/条例 主要内容
2003年3月 NMPA 人基因治疗研究和制剂质量控制技术指导原则 从申报资料角度对其提出要求,拟按照药品进行管理。基本原则:(1) 必须确保安全有效,充分估计风险,提出相应质控要求;(2) 促进基因治疗研究,加强创新
2009年5月 卫生部 医疗技术临床应用管理办法 将基因治疗列为第三类医疗技术目录,后于2015年6月取消第三类医疗技术临床应用准入审批,医院成为第三类技术治疗和安全管理的责任主体
2017年12月 NMPA 细胞治疗产品研究与评价技术指导原则(试行) 规范和指导按照药品研发及注册的细胞治疗产品的研究与评价工作
2019年2月 卫健委 生物医学新技术临床应用管理条例(征求意见稿) 生物医学新技术临床研究必须经行政审批
2019年3月 卫健委 体细胞治疗临床研究和转化应用管理办法(试行) 以医疗机构为责任主体,为满足临床需求,规范和促进体细胞治疗临床研究和转化应用
Table 4 Pertinent regulations of gene therapy in China
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