Carboxymethyl chitosan prolongs adenovirus-mediated expression of IL-10 and ameliorates hepatic fibrosis in a mouse model

作者全名："Gou, Yannian; Weng, Yaguang; Chen, Qian; Wu, Jinghong; Wang, Hao; Zhong, Jiamin; Bi, Yang; Cao, Daigui; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Wagstaff, William; Hendren-Santiago, Bryce; Chen, Connie; Youssef, Andrew; Haydon, Rex C.; Luu, Hue H.; Reid, Russell R.; Shen, Le; He, Tong-Chuan; Fan, Jiaming"

作者地址："[Gou, Yannian; Weng, Yaguang; Wu, Jinghong; Wang, Hao; Zhong, Jiamin; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Fan, Jiaming] Chongqing Med Univ, Sch Lab Med, Minist Educ, Key Lab Diagnost Med, Chongqing, Peoples R China; [Gou, Yannian; Weng, Yaguang; Wu, Jinghong; Wang, Hao; Zhong, Jiamin; Zhao, Piao; Dong, Xiangyu; Guo, Meichun; Fan, Jiaming] Chongqing Med Univ, Sch Lab Med, Dept Clin Biochem, Chongqing, Peoples R China; [Gou, Yannian; Wang, Hao; Zhong, Jiamin; Bi, Yang; Cao, Daigui; Zhao, Piao; Wagstaff, William; Hendren-Santiago, Bryce; Chen, Connie; Youssef, Andrew; Haydon, Rex C.; Luu, Hue H.; Reid, Russell R.; Shen, Le; He, Tong-Chuan; Fan, Jiaming] Univ Chicago, Mol Oncol Lab, Dept Orthopaed Surg & Rehabil Med, Med Ctr, Chicago, IL 60637 USA; [Chen, Qian] Deyang Peoples Hosp, Hlth Management Ctr, Deyang, Peoples R China; [Bi, Yang] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Stem Cell Biol & Therapy Lab, Pediat Res Inst,Childrens Hosp, Chongqing, Peoples R China; [Bi, Yang] Chongqing Med Univ, Key Lab Child Dev & Disorders, Minist Educ, Childrens Hosp, Chongqing, Peoples R China; [Cao, Daigui] Affiliated Hosp Univ Chinese Acad Sci, Dept Orthopaed Surg, Chongqing, Peoples R China; [Cao, Daigui] Chongqing Gen Hosp, Chongqing, Peoples R China; [Zhao, Piao] Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 1, Chongqing, Peoples R China; [Reid, Russell R.; He, Tong-Chuan] Univ Chicago, Lab Craniofacial Suture Biol & Dev, Dept Surg, Sect Plast Surg,Med Ctr, Chicago, IL 60637 USA; [Shen, Le; He, Tong-Chuan] Univ Chicago, Med Ctr, Dept Surg, Chicago, IL 60637 USA"

通信作者："He, TC; Fan, JM (通讯作者)，Univ Chicago, Mol Oncol Lab, Med Ctr, Chicago, IL 60637 USA.; Fan, JM (通讯作者)，Chongqing Med Univ, Sch Lab Med, Dept Clin Biochem, Minist Educ,Key Lab Diagnost Med, Chongqing 400016, Peoples R China."

来源：BIOENGINEERING & TRANSLATIONAL MEDICINE

ESI学科分类：Multidisciplinary

WOS号：WOS:000766486000001

JCR分区：Q1

影响因子：7.4

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：adenovirus vector; carboxymethyl chitosan (CMC); chitosan; chitosan; gene delivery; gene therapy; hepatic fibrosis; host immune response

摘要："Effective and safe liver-directed gene therapy has great promise in treating a broad range of liver diseases. While adenoviral (Ad) vectors have been widely used for efficacious in vivo gene delivery, their translational utilities are severely limited due to the short duration of transgene expression and solicitation of host immune response. Used as a promising polymeric vehicle for drug release and nucleic acid delivery, carboxymethyl chitosan (CMC) is biocompatible, biodegradable, anti-microbial, inexpensive, and easy accessible. Here, by exploiting its biocompatibility, controlled release capability and anti-inflammatory activity, we investigated whether CMC can overcome the shortcomings of Ad-mediated gene delivery, hence improving the prospect of Ad applications in gene therapy. We demonstrated that in the presence of optimal concentrations of CMC, Ad-mediated transgene expression lasted up to 50 days after subcutaneous injection, and at least 7 days after intrahepatic injection. Histologic evaluation and immunohistochemical analysis revealed that CMC effectively alleviated Ad-induced host immune response. In our proof-of-principle experiment using the CCl4-induced experimental mouse model of chronic liver damage, we demonstrated that repeated intrahepatic administrations of Ad-IL10 mixed with CMC effectively mitigated the development of hepatic fibrosis. Collectively, these results indicate that CMC can improve the prospect of Ad-mediated gene therapy by diminishing the host immune response while allowing readministration and sustained transgene expression."

基金机构："2019 Chongqing Support Program for Entrepreneurship and Innovation [cx2019113]; Chongqing Human Resources and Social Security Bureau [298]; 2019 Science and Technology Research Plan Project of Chongqing Education Commission [KJQN201900410]; 2019 Youth Innovative Talent Training Program of Chongqing Education Commission [CY200409]; National Institutes of Health [P30CA014599, T32 GM007281, UL1 TR000430]; National Natural Science Foundation of China [82102696]"

基金资助正文："2019 Chongqing Support Program for Entrepreneurship and Innovation, Grant/Award Number: cx2019113; 2019 Funding for Postdoctoral Research, Chongqing Human Resources and Social Security Bureau, Grant/Award Number: 298; 2019 Science and Technology Research Plan Project of Chongqing Education Commission, Grant/Award Number: KJQN201900410; 2019 Youth Innovative Talent Training Program of Chongqing Education Commission, Grant/Award Number: CY200409; National Institutes of Health, Grant/Award Numbers: P30CA014599, T32 GM007281, UL1 TR000430; National Natural Science Foundation of China, Grant/Award Number: 82102696"