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^-1 GC304 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^-1 GC304 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