[1]王晓,黄晓平,黎玲,等.C5-12启动子降低rAAV1介导的基因递送后转基因的免疫反应[J].华侨大学学报(自然科学版),2025,46(4):435-441.[doi:10.11830/ISSN.1000-5013.202412014]
 WANG Xiao,HUANG Xiaoping,LI Ling,et al.C5-12 Promoter Reduces Transgene Immune Response Following rAAV1-Mediated Gene Delivery[J].Journal of Huaqiao University(Natural Science),2025,46(4):435-441.[doi:10.11830/ISSN.1000-5013.202412014]
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C5-12启动子降低rAAV1介导的基因递送后转基因的免疫反应()
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《华侨大学学报(自然科学版)》[ISSN:1000-5013/CN:35-1079/N]

卷:
第46卷
期数:
2025年第4期
页码:
435-441
栏目:
出版日期:
2025-07-16

文章信息/Info

Title:
C5-12 Promoter Reduces Transgene Immune Response Following rAAV1-Mediated Gene Delivery
文章编号:
1000-5013(2025)04-0435-07
作者:
王晓1 黄晓平2 黎玲1 张红1 刁勇1
1. 华侨大学 医学院, 福建 泉州 362021;2. 泉州师范学院 化工与材料学院, 福建 泉州 362000
Author(s):
WANG Xiao1 HUANG Xiaoping2 LI Ling1ZHANG Hong1 DIAO Yong1
1. School of Medicine, Huaqiao University, Quanzhou 362021, China; 2. College of Chemical Engineering and Materials Sciences, Quanzhou Normal University, Quanzhou 362000, China
关键词:
C5-12启动子 重组腺相关病毒(rAAV) 免疫反应 转基因 卵清蛋白(OVA)
Keywords:
C5-12 promoter recombinant adeno-associated virus(rAAV) immune response transgene ovalbumin(OVA)
分类号:
Q78
DOI:
10.11830/ISSN.1000-5013.202412014
文献标志码:
A
摘要:
通过转基因表达测定、体外抗原递呈、转导阳性细胞清除等实验,探索C5-12启动子在减少或消除针对卵清蛋白(OVA)的免疫反应的作用。实验结果表明:在小鼠成肌细胞C2C12中,C5-12启动子不影响OVA的表达,而在小鼠骨髓树突状细胞JAWS Ⅱ中,C5-12启动子显著抑制OVA表达和OVA抗原肽的递呈;肌肉给药后,C5-12启动子能维持OVA在肌肉组织中持续高表达,体液免疫维持较低水平,肌肉组织中免疫反应较轻且转导阳性细胞清除明显减少。
Abstract:
The efficacy of the C5-12 promoter in reducing or abolishing the immune response against ovalbumin(OVA)was explored through experiments such as determination of transgene expression, in vitro antigen presentation, and the clearance of transduced positive cells. The experimental results showed that in mouse myoblasts C2C12, the C5-12 promoter had no impact on the expression of OVA, while in mouse bone marrow dendritic cells JAWS Ⅱ, the C5-12 promoter significantly inhibited both the expression of OVA and the presentation of OVA antigenic peptides. After muscle administration, the C5-12 promoter could maintain the continuous high expression of OVA in muscle tissues, the humoral immunity remained at a relatively low level, the immune response in muscle tissues was relatively mild, and the clearance of transduced positive cells was significantly reduced.

参考文献/References:

[1] WANG Dan,ZHONG Li,ABU N M,et al.The potential of adeno-associated viral vectors for gene delivery to muscle tissue[J].Expert Opinion on Drug Delivery,2014,11(3):345-364.DOI:10.1517/17425247.2014.871258.
[2] HUANG Xiaoping,WANG Xiao,LI Ling,et al.MiR133b-mediated inhibition of EGFR-PTK pathway promotes rAAV2 transduction by facilitating intracellular trafficking and augmenting second-strand synthesis[J].Journal of Cellular and Molecular Medicine,2023,27(18):2714-2729.DOI:10.1111/jcmm.17858.
[3] HUANG Xiaoping,WANG Xiao,REN Yanxuan,et al.Reactive oxygen species enhance rAAV transduction by promoting its escape from late endosomes[J].Virology Journal,2023,20(1):2.DOI:10.1186/s12985-023-01964-w.
[4] SHEN Weiran,LIU Shengjiang,OU Li.rAAV immunogenicity, toxicity, and durability in 255 clinical trials: A meta-analysis[J].Frontiers in Immunology,2022,13:1001263.DOI:10.3389/fimmu.2022.1001263.
[5] 刁勇,王启钊,肖卫东,等.重组腺相关病毒基因药物的细胞免疫毒性及对策[J].药学学报,2010,45(9):1071-1077.DOI:10.16438/j.0513-4870.2010.09.009.
[6] 刁勇,许瑞安.重组腺相关病毒载体诱导的天然免疫反应及机制[J].微生物学报,2012,52(5):550-557.DOI:10.13343/j.cnki.wsxb.2012.05.002.
[7] 王晓,黄晓平,黎玲,等.氧化应激促进重组腺相关病毒2型体外转导分析[J].华侨大学学报(自然科学版),2022,43(4):489-497.DOI:10.11830/ISSN.1000-5013.202201036.
[8] SAMULSKI R J,MUZYCZKA N.AAV-mediated gene therapy for research and therapeutic purposes[J].Annual Review of Virology,2014,1(1):427-451.DOI:10.1146/annurev-virology-031413-085355.
[9] BALAZS A B,CHEN J,HONG C M,et al.Antibody-based protection against HIV infection by vectored immunoprophylaxis[J].Nature,2011,481(7379):81-84.DOI:10.1038/nature10660.
[10] FUCHS S P,MARTINEZ-NAVIO J M,PIATAK M,et al.AAV-delivered antibody mediates significant protective effects against SIVmac239 challenge in the absence of neutralizing activity[J].Plos Pathogens,2015,11(8):e1005090.DOI:10.1371/journal.ppat.1005090.
[11] JOHNSON P R,SCHNEPP B C,ZHANG Jianchao,et al.Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys[J].Nature Medicine,2009,15(8):901-906.DOI:10.1038/nm.1967.
[12] DE JONG Y P,DORNE M,MOMMERSTEEG M C,et al.Broadly neutralizing antibodies abrogate established hepatitis C virus infection[J].Science Translational Medicine,2014,6(254):254ra129.DOI:10.1126/scitranslmed.3009512.
[13] DEAL C,BALAZS A B,ESPINOSA D A,et al.Vectored antibody gene delivery protects against Plasmodium falciparum sporozoite challenge in mice[J].Proceedings of the Nationall Academy of Sciences of the United States of America,2014,111(34):12528-12532.DOI:10.1073/pnas.1407362111.
[14] LIMBERIS M P,ADAM V S,WONG G,et al.Intranasal antibody gene transfer in mice and ferrets elicits broad protection against pandemic influenza[J].Science Translational Medicine,2013,5(187):187ra172.DOI:10.1126/scitranslmed.3006299.
[15] BOENNEMANN C G,BELLUSCIO B A,BRAUN S,et al.Dystrophin immunity after gene therapy for duchenne’s muscular dystrophy[J].New England Journal of Medicine,2023,388(24):2294-2296.DOI:10.1056/NEJMc 2212912.
[16] CHENUAUD P,LARCHER T,RABINOWITZ J E,et al.Autoimmune anemia in macaques following erythropoietin gene therapy[J].Blood,2004,103(9):3303-3304.DOI:10.1182/blood-2003-11-3845.
[17] GAO Guangping,LEBHERZ C,WEINER D J,et al.Erythropoietin gene therapy leads to autoimmune anemia in macaques[J].Blood,2004,103(9):3300-3302.DOI:10.1182/blood-2003-11-3852.
[18] JOOSS K,YANG Y,FISHER K J,et al.Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers[J].Journal of Virology,1998,72(5):4212-4223.DOI:10.1128/JVI.72.5.4212-4223.1998.
[19] MAYS L E,WILSON J M.The complex and evolving story of T cell activation to AAV vector-encoded transgene products[J].Molecular Therapy,2011,19(1):16-27.DOI:10.1038/mt.2010.250.
[20] DRAGHIA-AKLI R,FIOROTTO M L,HILL L A,et al.Myogenic expression of an injectable protease-resistant growth hormone-releasing hormone augments long-term growth in pigs[J].Nature Biotechnology,1999,17(12):1179-1183.DOI:10.1038/70718.
[21] LI Xuyang,EASTMAN E M,SCHWARTZ R J,et al.Synthetic muscle promoters: Activities exceeding naturally occurring regulatory sequences[J].Nature Biotechnology,1999,17(3):241-245.DOI:10.1038/6981.
[22] LIU Yilin,MINGOZZI F,RODRIGUEZ-COLON S M,et al.Therapeutic levels of factor IX expression using a muscle-specific promoter and adeno-associated virus serotype 1 vector[J].Human Gene Therapy,2004,15(8):783-792.DOI:10.1089/1043034041648453.
[23] PUPO A,FERNANDEZ A,LOW S H,et al.AAV vectors: The Rubik’s cube of human gene therapy[J].Molecular Therapy,2022,30(12):3515-3541.DOI:10.1016/j.ymthe.2022.09.015.
[24] SCHULZ M,LEVY D I,PETROPOULOS C J,et al.Binding and neutralizing anti-AAV antibodies: Detection and implications for rAAV-mediated gene therapy[J].Molecular Therapy,2023,31(3):616-630.DOI:10.1016/j.ymthe.2023.01.010.
[25] WANG Jianghui,GESSLER D J,ZHAN Wei,et al.Adeno-associated virus as a delivery vector for gene therapy of human diseases[J].Signal Transduction and Targeted Therapy,2024,9(1):78.DOI:10.1038/s41392-024-01780-w.
[26] GAUDET D,DE WAL J,TREMBLAY K,et al.Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency[J].Atherosclerosis Supplements,2010,11(1):55-60.DOI:10.1016/j.atherosclerosissup.2010.03.004.
[27] GAUDET D,METHOT J,KASTELEIN J.Gene therapy for lipoprotein lipase deficiency[J].Current Opinion In Lipidology,2012,23(4):310-320.DOI:10.1097/MOL.0b013e3283555a7e.
[28] MAGUIRE A M,HIGH K A,AURICCHIO A,et al.Age-dependent effects of RPE65 gene therapy for Leber’s congenital amaurosis: A phase 1 dose-escalation trial[J].Lancet,2009,374(9701):1597-1605.DOI:10.1016/s0140-6736(09)61836-5.
[29] NATHWANI A C,ROSALES C,MCLNTOSH J,et al.Long-term safety and efficacy following systemic administration of a self-complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins[J].Molecular Therapy,2011,19(5):876-885.DOI:10.1038/mt.2010.274.
[30] HANLEY J P,JARVIS L M,ANDREWS J,et al.Investigation of chronic hepatitis C infection in individuals with haemophilia: Assessment of invasive and non-invasive methods[J].British Journal of Haematology,1996,94(1):159-165.DOI:10.1046/j.1365-2141.1996.6192064.x.
[31] MANNO C S,CHEW A J,HUTCHISON S,et al.AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B[J].Blood,2003,101(8):2963-2972.DOI:10.1182/blood-2002-10-3296.
[32] MENDELL J R,RODINO-KLAPAC L,SAHENK Z,et al.Gene therapy for muscular dystrophy: Lessons learned and path forward[J].Neuroscience Letters,2012,527(2):90-99.DOI:10.1016/j.neulet.2012.04.078.
[33] YUASA K,SAKAMOTO M,MIYAGOE-SUZUKI Y,et al.Adeno-associated virus vector-mediated gene transfer into dystrophin-deficient skeletal muscles evokes enhanced immune response against the transgene product[J].Gene Therapy,2002,9(23):1576-1588.DOI:10.1038/sj.gt.3301829.
[34] KESSLER P D,PODSAKOFF G M,CHEN Xiaojuan,et al.Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein[J].Proceedings of the National Academy of Sciences of the United States of America,1996,93(24):14082-14087.DOI:10.1073/pnas.93.24.14082.
[35] ARRUDA V R,FAVARO P,FINN J D.Strategies to modulate immune responses: A new frontier for gene therapy[J].Molecular Therapy,2009,17(9):1492-1503.DOI:10.1038/mt.2009.150.
[36] BOENNEMANN C G,BELLUSCIO B A,BRAUN S,et al.Dystrophin immunity after gene therapy for duchenne’s muscular dystrophy[J].New England Journal of Medicine,2023,388(24):2294-2296.DOI:10.1056/NEJMc 2212912.
[37] HOFFMAN B E,DOBRZYNSKI E,WANG Lixin,et al.Muscle as a target for supplementary factor IX gene transfer[J].Human Gene Therapy,2007,18(7):603-613.DOI:10.1089/hum.2007.042.
[38] MUHURI M,ZHAN Wei,MAEDA Y,et al.Novel combinatorial microRNA-binding sites in AAV vectors synergistically diminish antigen presentation and transgene immunity for efficient and stable transduction[J].Front Immunol,2021,12:674242.DOI:10.3389/fimmu.2021.674242.
[39] XIAO Yuanyuan,MUHURI M,LI Shaoyong,et al.Circumventing cellular immunity by miR142-mediated regulation sufficiently supports rAAV-delivered OVA expression without activating humoral immunity[J].JCI Insight,2019,5(13):1-14.DOI:10.1172/jci.insight.99052.
  

备注/Memo

备注/Memo:
收稿日期: 2024-12-20
通信作者: 刁勇(1967-),男,教授,博士,博士生导师,主要从事基因药物的研究。E-mail:diaoyong@hqu.edu.cn。
基金项目: 国家自然科学基金资助项目(81502687, 81371669); 福建省自然科学基金资助项目(2021J01439); 福建省泉州市科技计划项目(2020C061); 福建省高等教育协会2022年高等教育科学研究实验室研究专项(22FJSYYB006)
更新日期/Last Update: 2025-07-20