摘要
Gene therapy is expected to fundamentally correct mutant genes to cure genetic diseases in vivo.As a delivery system for gene therapy,adenovirus-associated virus(AAV)vectors have achieved positive results in clinical and preclinical research,including the treatment of genetic diseases,such as those affecting the blood and eyes[1].
新兴的CRISPR/Cas系统因其高效性和便捷性已成为目前最常用的基因编辑工具,并有望在体内基因治疗研究中发挥重要作用.AAV递送系统和CRISPR编辑系统是开展体内基因治疗的重要元件,然而,有研究发现人体中具有针对AAV和Cas9蛋白的预存抗体,说明免疫反应是基因修复治疗必须面对的问题.本研究检测到猕猴(恒河猴和食蟹猴)体内普遍存在针对AAV(包括AAV2、AAV8和AAV9)和Cas蛋白(包括SaCas9、SpCas9、AsCas12a和LbCas12a)的预存抗体.当给小鼠和猕猴体内注射了AAV9或SpCas9蛋白后,均激发了一系列的免疫反应.此外,猕猴体内AAV携带Cas9基因的治疗试验也显示体液免疫反应被激活.上述研究结果进一步证实猕猴与人类似,体内普遍存在AAV和Cas蛋白的预存抗体,且AAV-CRISPR体内基因治疗会引发相应的免疫应答.
基金
supported by the National Natural Science Foundation of China(81930121 and U1602224)
the National Key Research and Development Program of China(2018YFA0107902,2017YFC1001902,and 2018YFA0801403)
the Yunnan Fundamental Research Projects(2019FY002 and 2018FB114)
the Major Basic Research Project of Science and Technology of Yunnan(202001BC070001)。
