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目的给恒河猴膝关节腔注射rAAV2/hTNFR:Fc,观察rAAV2/hTNFR:Fc对机体产生的毒性反应及其严重程度、主要毒性靶器官以及损害的可逆程度。方法设PBS对照组、rAAV2/hTNFR:Fc低剂量组和rAAV2/hTNFR:Fc高剂量组,除PBS对照组给予等体积PBS外,rAAV2/hTNFR:Fc低剂量组和高剂量组分别给予1×1012vg/ml、3×1012vg/ml的供试品。均按1ml/只关节腔注射,连续8d,随后观察6个月。结果心电图、尿生化、体温、血液学和血清生化学指标等均未见有明显改变,病理学检查也未发现供试品相关的大体病理学改变和组织病理学改变。给恒河猴膝关节腔注射供试品rAAV2/hTNFR:Fc的主要分布组织为:关节腔滑膜、脾脏和淋巴结,高剂量在肝脏和肺脏有非常低浓度的分布,随时间延长,供试品在各组织的分布浓度有缓慢下降的趋势。结论给恒河猴膝关节腔注射供试品rAAV2/hTNFR:Fc,连续给药8d,无明显毒副反应剂量大于3×1012vg/只。
Objective To observe rAAV2 / hTNFR: Fc injection into rhesus monkey knee joint cavity and to observe the toxicity and severity of rAAV2 / hTNFR: Fc to the body, the main toxic target organs and the degree of reversibility of damage. Methods The PBS rAAV2 / hTNFR: Fc low dose group and the rAAV2 / hTNFR: Fc high dose group were given PBS with the same volume of PBS, rAAV2 / hTNFR: Fc low dose group and high dose group were given 1 × 1012vg / ml, 3 × 1012vg / ml of the test article. According to 1ml / only intra-articular injection, continuous 8d, followed by observation of 6 months. Results Electrocardiogram, urine biochemistry, body temperature, hematology and serum biochemical indicators were not significantly changed, the pathological examination did not find the test for the general pathological changes and histopathological changes. The rAAV2 / hTNFR: Fc is mainly distributed in synovial membrane, spleen and lymph node of rhesus monkey. The high dose has a very low concentration distribution in the liver and lung, Distribution of products in various organizations have a slow decline in the trend. Conclusions Rhesus monkey can be injected with rAAV2 / hTNFR: Fc into the knee joint cavity continuously for 8 days without significant toxic side effects more than 3 × 1012vg / body.