The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver
The multi-administration of recombinant adeno-associated virus (rAAV) is limited largely by immunological barriers. Herein, a novel strategy, named rAAV pseudo-lipid nanoparticle combined with triamcinolone acetonide (LNP-rAAV + TAC), has been described in mice. We showed successful but low efficien...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
|
| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124002158 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832595835705098240 |
|---|---|
| author | Chunmei Gan Mi Leng Yu Liu Zhaoyue Zheng Siwu He Wen Qiao Lin Xiao Yao Xiao Jingya Ye Lixing Zhou Jiao Zhou Boduan Xiao Wenxin Zhao Jiamei Yang Aohan Wu Huiyuan Zhang Hongbo Hu Xiaobo Cen Zhiyong Qian Haohao Dong C. Alexander Valencia Lunzhi Dai Hoi Yee Chow Lei Zhang Biao Dong |
| author_facet | Chunmei Gan Mi Leng Yu Liu Zhaoyue Zheng Siwu He Wen Qiao Lin Xiao Yao Xiao Jingya Ye Lixing Zhou Jiao Zhou Boduan Xiao Wenxin Zhao Jiamei Yang Aohan Wu Huiyuan Zhang Hongbo Hu Xiaobo Cen Zhiyong Qian Haohao Dong C. Alexander Valencia Lunzhi Dai Hoi Yee Chow Lei Zhang Biao Dong |
| author_sort | Chunmei Gan |
| collection | DOAJ |
| description | The multi-administration of recombinant adeno-associated virus (rAAV) is limited largely by immunological barriers. Herein, a novel strategy, named rAAV pseudo-lipid nanoparticle combined with triamcinolone acetonide (LNP-rAAV + TAC), has been described in mice. We showed successful but low efficient triple trafficking by LNP-rAAV2 carrying EGFP, human factor IX (hFIX), and luciferase (luc), due to its encapsulation characteristic. Additionally, sustained TAC treatment, which dose-dependently downregulated the anti-rAAV2 antibodies, permitted rAAV2 re-administration at dosages of ≥45 mg/kg/3 days. Furthermore, to improve the efficiency and safety, LNP-rAAV + TAC was evaluated, using LNP-rAAV2 carrying EGFP, hFIX, and luc co-treating with 45 mg/kg/3 days TAC before and after treatment with LNP-rAAV2 injections. Notable neutralizing antibody reductions of 37.8-fold and 12.7-fold were observed by the combinatorial strategy compared with the independent LNP encapsulation and TAC treatment approaches. The plasma hFIX protein was enhanced to 15.1 μg/mL and the liver bioluminescence was elevated to 1.4 × 108 p/s/cm2/sr following the second and third administrations, with weaker levels in LNP encapsulation (1.9 μg/mL, 2.1 × 104 p/s/cm2/sr) and TAC treatment (3.0 μg/mL, 6.1 × 104 p/s/cm2/sr) groups. Thus, this combination strategy is an attractive candidate for enabling multi-dosing of rAAV vector and warrants further study on the underlying mechanism. |
| format | Article |
| id | doaj-art-e600824c6c1b44acb14b30e69690dab5 |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-e600824c6c1b44acb14b30e69690dab52025-01-18T05:04:46ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012025-03-01331101399The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liverChunmei Gan0Mi Leng1Yu Liu2Zhaoyue Zheng3Siwu He4Wen Qiao5Lin Xiao6Yao Xiao7Jingya Ye8Lixing Zhou9Jiao Zhou10Boduan Xiao11Wenxin Zhao12Jiamei Yang13Aohan Wu14Huiyuan Zhang15Hongbo Hu16Xiaobo Cen17Zhiyong Qian18Haohao Dong19C. Alexander Valencia20Lunzhi Dai21Hoi Yee Chow22Lei Zhang23Biao Dong24National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Sichuan Real & Best Biotech Co., Ltd., Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Real & Best Biotech Co., Ltd., Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaSichuan Real & Best Biotech Co., Ltd., Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaHaitong International Capital Limited, Hong Kong, ChinaCenter for Hematology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaCenter for Hematology and Immunology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaWest China-Frontier Pharma Tech Co., Ltd., Chengdu, ChinaDepartment of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Sichuan Real & Best Biotech Co., Ltd., Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, ChinaNational Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Corresponding author: National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, Chinese Academy of Medical Sciences Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, China; Corresponding author: State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin Key Laboratory of Gene Therapy for Blood Diseases, Chinese Academy of Medical Sciences Key Laboratory of Gene Therapy for Blood Diseases, Tianjin, China.National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Sichuan Real & Best Biotech Co., Ltd., Chengdu, China; Corresponding author: National Clinical Research Center for Geriatrics and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.The multi-administration of recombinant adeno-associated virus (rAAV) is limited largely by immunological barriers. Herein, a novel strategy, named rAAV pseudo-lipid nanoparticle combined with triamcinolone acetonide (LNP-rAAV + TAC), has been described in mice. We showed successful but low efficient triple trafficking by LNP-rAAV2 carrying EGFP, human factor IX (hFIX), and luciferase (luc), due to its encapsulation characteristic. Additionally, sustained TAC treatment, which dose-dependently downregulated the anti-rAAV2 antibodies, permitted rAAV2 re-administration at dosages of ≥45 mg/kg/3 days. Furthermore, to improve the efficiency and safety, LNP-rAAV + TAC was evaluated, using LNP-rAAV2 carrying EGFP, hFIX, and luc co-treating with 45 mg/kg/3 days TAC before and after treatment with LNP-rAAV2 injections. Notable neutralizing antibody reductions of 37.8-fold and 12.7-fold were observed by the combinatorial strategy compared with the independent LNP encapsulation and TAC treatment approaches. The plasma hFIX protein was enhanced to 15.1 μg/mL and the liver bioluminescence was elevated to 1.4 × 108 p/s/cm2/sr following the second and third administrations, with weaker levels in LNP encapsulation (1.9 μg/mL, 2.1 × 104 p/s/cm2/sr) and TAC treatment (3.0 μg/mL, 6.1 × 104 p/s/cm2/sr) groups. Thus, this combination strategy is an attractive candidate for enabling multi-dosing of rAAV vector and warrants further study on the underlying mechanism.http://www.sciencedirect.com/science/article/pii/S2329050124002158recombinant adeno-associated viruslipid nanoparticlecorticosteroidimmunosuppressionmultiple systemic administration |
| spellingShingle | Chunmei Gan Mi Leng Yu Liu Zhaoyue Zheng Siwu He Wen Qiao Lin Xiao Yao Xiao Jingya Ye Lixing Zhou Jiao Zhou Boduan Xiao Wenxin Zhao Jiamei Yang Aohan Wu Huiyuan Zhang Hongbo Hu Xiaobo Cen Zhiyong Qian Haohao Dong C. Alexander Valencia Lunzhi Dai Hoi Yee Chow Lei Zhang Biao Dong The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver Molecular Therapy: Methods & Clinical Development recombinant adeno-associated virus lipid nanoparticle corticosteroid immunosuppression multiple systemic administration |
| title | The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver |
| title_full | The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver |
| title_fullStr | The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver |
| title_full_unstemmed | The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver |
| title_short | The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver |
| title_sort | combination of raav pseudo lipid nanoparticle and triamcinolone acetonide enables multi administration to liver |
| topic | recombinant adeno-associated virus lipid nanoparticle corticosteroid immunosuppression multiple systemic administration |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124002158 |
| work_keys_str_mv | AT chunmeigan thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT mileng thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT yuliu thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT zhaoyuezheng thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT siwuhe thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT wenqiao thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT linxiao thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT yaoxiao thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jingyaye thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT lixingzhou thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jiaozhou thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT boduanxiao thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT wenxinzhao thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jiameiyang thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT aohanwu thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT huiyuanzhang thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT hongbohu thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT xiaobocen thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT zhiyongqian thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT haohaodong thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT calexandervalencia thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT lunzhidai thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT hoiyeechow thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT leizhang thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT biaodong thecombinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT chunmeigan combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT mileng combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT yuliu combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT zhaoyuezheng combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT siwuhe combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT wenqiao combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT linxiao combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT yaoxiao combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jingyaye combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT lixingzhou combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jiaozhou combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT boduanxiao combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT wenxinzhao combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT jiameiyang combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT aohanwu combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT huiyuanzhang combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT hongbohu combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT xiaobocen combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT zhiyongqian combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT haohaodong combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT calexandervalencia combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT lunzhidai combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT hoiyeechow combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT leizhang combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver AT biaodong combinationofraavpseudolipidnanoparticleandtriamcinoloneacetonideenablesmultiadministrationtoliver |