Biodistribution Study of Gene Therapy Pharmaceutical rAAV2-sTRAIL in Mice
WANG Xin1, LI Wei1, ZHENG De-xian2, WANG Chao1, MIAO Yu-fa1, ZHOU Xiao-bing1, WANG San-long1, LI Bo1, HUO Yan1*
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1. National Center for Safety Evaluation of Drugs, National Institute for Food and Drug Control, The Beijing Key Lab for Pre-clinical Safety Evaluation of Drugs, Beijing 100176, China; 2. Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China
OBJECTIVE To conduct biodistribution studies of gene therapy pharmaceutical rAAV2-sTRAIL in both normal and tumor bearing BALB/c mice. METHODS BALB/c mice were divided randomly into three groups including vehicle control group(0 vg) with eight animals per sex, low-dose (1.5×109 vg) and high-dose (1.5×1010 vg) groups with 20 animals per sex for each group. The mice were administered the test drug intramuscularly once and observed for clinical symptoms daily and dissected at 24 h, 2, 4,12 week to get organs. BALB/c nude mice were transplanted ACC-2 cells at armpit of right fore to form tumor block which was considered appropriately to use when most of them grew up to 100 mm3. Tumor bearing mice were sorted into three groups according to tumor size, which were vehicle control group(0 vg) with four animals per sex, low-dose (1.5×109 vg) and high-dose (1.5×1010 vg) groups with ten animals per sex for each group.The mice were administered the test drug intratumorally once and dissected at 24 h and 2week after dosing. Blood, testis (uterus), epididymis (ovary), kidney, spleen, small intestine, mesenteric glands, liver, stomach, lung, heart, brain, injection site (muscle or tumor), sternum marrow were collected from each animal of normal or tumor model. DNA of tissues was extracted and test article copies in it were detectedwith Taqman external standard method. RESULTS The normal experiment showed that the target organs were spleen, small intestine, mesenteric glands, liver, lung, muscle, sternum marrow, blood and the test drug mainly concentrated in spleen, liver and injection site. Drugs were cleared up with time extending and were not accumulated in the body. Tumor model experiment showed similar results in distribution and elimination features, and the test articles didnot exhibit reproducibility in tumor and other organs. CONCLUSION The gene therapy pharmaceutical rAAV2-sTRAIL showed similar distribution characteristic in normal and tumor bearing BALB/c mice, and were not reproducible and accumulative in the body. Our work helps to forecast rAAV2-sTRAIL safety preliminarily for clinical use and give suggestive information for clinical trial design.
WANG Xin, LI Wei, ZHENG De-xian, WANG Chao, MIAO Yu-fa, ZHOU Xiao-bing, WANG San-long, LI Bo, HUO Yan.
Biodistribution Study of Gene Therapy Pharmaceutical rAAV2-sTRAIL in Mice[J]. Chinese Pharmaceutical Journal, 2021, 56(13): 1076-1082 https://doi.org/10.11669/cpj.2021.13.010
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