The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver

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...

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Main Authors: 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
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:Molecular Therapy: Methods & Clinical Development
Subjects:
recombinant adeno-associated virus
lipid nanoparticle
corticosteroid
immunosuppression
multiple systemic administration
Online Access:http://www.sciencedirect.com/science/article/pii/S2329050124002158
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Summary: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.
ISSN:2329-0501

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