文献类型：期刊文献

英文题名：Repeated Systemic Dosing of Adeno-Associated Virus Vectors in Immunocompetent Mice After Blockade of T Cell Costimulatory Pathways

作者：Zhong, Chen[1];Jiang, Wei[2];Wang, Yefan[2];Sun, Junjiang[3,4];Wu, Xia[2];Zhuang, Yingping[1];Xiao, Xiao[1,2]

机构：[1]East China Univ Sci & Technol, Sch Biotechnol, State Key Lab Bioreactor Engn, 130 Meilong Rd, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China;[3]Univ N Carolina, Gene Therapy Ctr, Chapel Hill, NC 27515 USA;[4]Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27515 USA

年份：2022

卷号：33

期号：5-6

起止页码：290

外文期刊名：HUMAN GENE THERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000738886900001)】；

基金：This work was supported by the Fundamental Research Funds for the Central Universities (grant no. 81970171).

语种：英文

外文关键词：CTLA4-Ig; CD40-Ig; AAV; multiple systemic administration; immune tolerance

摘要：Neutralizing antibodies (NAbs) strongly limit adeno-associated virus (AAV) vector transduction and repeated administration. Previous studies have shown that NAbs induced by AAVs are associated with T and B cell activation and that the B7/CD28 and CD40/CD40L costimulation signaling pathways are involved. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and CD40 are vital molecules that participate in the costimulatory pathway. In this study, we evaluated CTLA4-Ig and CD40-Ig immunosuppreve efficacies through AAV and investigated their effects on the feasibility for multiple systemic administrations of AAV vectors. The results showed that a single administration of AAV vector carrying either CTLA4-Ig alone or with CD40-Ig could greatly reduce the level of NAbs. An AAV serotype-specific immune tolerance could be successfully established, which enabled repeated, that is, second and third, systemic administration of AAV vectors in the same mice. A combination of CTLA4-Ig and CD40-Ig delivered via AAV vectors significantly inhibited T and B cell activations without affecting the immune response to the total immunoglobulin G production and cytokines. Interestingly, exogenous gene expression significantly improved after multiple administrations of AAV vector in vivo. Our study generates a reliable and effective method for repeated dosing of AAV vectors that is needed on gene therapy.