基因治疗药物AAV5-脂蛋白脂酶变异体临床前神经系统安全性评价

doi:10.19803/j.1672-8629.20220587

中国药物警戒 ›› 2023, Vol. 20 ›› Issue (1): 34-39.
DOI: 10.19803/j.1672-8629.20220587

• 基因治疗产品安全性评价专栏 • 上一篇下一篇

基因治疗药物AAV5-脂蛋白脂酶变异体临床前神经系统安全性评价

李芊芊¹, 夏艳^2∆, 侯田田¹, 王超¹, 石茜茜¹, 马雪梅², 刘子洋², 张颖丽¹, 吴小兵², 王三龙^1,*, 刘国庆^2#, 耿兴超¹

¹中国食品药品检定研究院,国家药物安全评价监测中心,药物非临床研究北京市重点实验室,北京100171;
²北京锦篮基因科技有限公司,北京 100176

收稿日期:2022-10-09 发布日期:2023-01-19
通讯作者: ^*王三龙,男,博士,主任药师,药物安全评价。E-mail: wangsanlong@nifdc.org.cn
^#为共同通信作者。
作者简介:李芊芊,女,博士,副主任药师,药物安全评价。
^△为并列第一作者。
基金资助:
国家重点研发计划（2021YFA1101602）

Nonclinical evaluation of safety of gene therapy drug AAV5 lipoprotein lipase variant (GC304) in the nervous system

LI Qianqian¹, XIA Yan^2∆, HOU Tiantian¹, WANG Chao¹, SHI Xixi¹, MA Xuemei², LIU Ziyang², ZHANG Yingli¹, WU Xiaobing², WANG Sanlong^1,*, LIU Guoqing^2#, GENG Xingchao¹

¹National Institutes For Food and drug control, National Center for Safety Evaluation of Drugs, Beijing Key Laboratory, Beijing 100171, China;
²Genecradle Therapeutics Inc, Beijing 100176, China

Received:2022-10-09 Published:2023-01-19

摘要/Abstract

摘要： 目的通过评价AAV5-脂蛋白脂酶变异体（GC304）腺相关病毒注射液对C57BL/6N小鼠中枢神经系统的影响,以确定受试物可能关系到人的安全性问题。方法共使用40只小鼠,雌雄各半,分别单次尾静脉给予溶媒对照、1.0×10¹³、5×10¹³、1.5×10¹⁴vg·kg^-1 GC304腺相关病毒注射液,采用功能观测组合试验方法（FOB）,分别在给药前和给药后1、4、24、48、96 h,7 、14 d观察小鼠运动功能、感觉功能、自主活动等行为,评价受试物对小鼠中枢神经系统的影响,并在给药后第14天检测血清TG、白蛋白和总蛋白改变。结果本研究前期,采用荧光定量PCR方法检测小鼠脑中目的基因（LPL）,其结果显示给予1.5×10¹⁴ vg·kg^-1 GC304 2周后,仍可在脑区内检测到目的基因（LPL）的拷贝数,基于上述数据开展了GC304行为学检测,其结果显示给予GC304后,可引起与药理作用相关的甘油三酯的明显降低,但在给药后2周内,GC304各剂量组动物笼内观察、手持观察、开放场观察、反射评价各指标均未见明显异常。结论 GC304可进入脑区,且给药后14 d内,目的基因在脑区内仍有少量分布,但其不会诱导产生神经毒性,为临床用药提供了参考。

关键词: 基因治疗, AAV5-脂蛋白脂酶变异体（GC304）, 功能观测组合试验方法, LPL, 神经毒性, 安全性, 小鼠

Abstract: Objective To determine the safety of GC304 in humans by focusing on evaluation of the effect of GC304 on the central nervous system of C57BL/6N mice. Methods A total of 40 mice, half male and half female, were given vehicle control and 1.0×10¹³, 5×10¹³, 1.5×10¹⁴ vg·kg^-1GC304 through the caudal vein respectively using the function observational battery (FOB) test method. The motor function, sensory function, autonomous activity and other behaviors of mice were observed before administration and 1 h, 4 h, 24 h, 48 h, 96 h, 7 d and 14 d after administration respectively. In addition, levels of TG, TP and ALB were detected 14 days after administration. Results The results of fluorescent quantitative PCR used in the early stage of this study showed that the copy number of the target genes could still be detected in the brain region two weeks after 1.5 ×10¹⁴ vg·kg^-1GC304 was given. Based on the above data, the behavioral study of GC304 was carried out. The results showed that after administration of GC304, triglycerides related to pharmacological effects could be significantly reduced. No obvious abnormalities were found during cage observation, hand-held observation, open field observation and reflex evaluation of animals in any of the dose groups of GC304 two weeks after administration. Conclusion GC304 can be directed into the brain region and a small number of target genes are still distributed in the brain region 14 days after administration, but GC304 will not induce neurotoxicity.

Key words: gene therapy, GC304, function observational battery, LPL, neurotoxicity, safety, mice

中图分类号:

R965.3

李芊芊, 夏艳, 侯田田, 王超, 石茜茜, 马雪梅, 刘子洋, 张颖丽, 吴小兵, 王三龙, 刘国庆, 耿兴超. 基因治疗药物AAV5-脂蛋白脂酶变异体临床前神经系统安全性评价[J]. 中国药物警戒, 2023, 20(1): 34-39.

LI Qianqian, XIA Yan, HOU Tiantian, WANG Chao, SHI Xixi, MA Xuemei, LIU Ziyang, ZHANG Yingli, WU Xiaobing, WANG Sanlong, LIU Guoqing, GENG Xingchao. Nonclinical evaluation of safety of gene therapy drug AAV5 lipoprotein lipase variant (GC304) in the nervous system[J]. Chinese Journal of Pharmacovigilance, 2023, 20(1): 34-39.

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基因治疗药物AAV5-脂蛋白脂酶变异体临床前神经系统安全性评价

Nonclinical evaluation of safety of gene therapy drug AAV5 lipoprotein lipase variant (GC304) in the nervous system

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