Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection  

作　　者：Wenjing Zai Min Yang Kuan Jiang Juan Guan Huijing Wang Kongying Hu Chao Huang Jieliang Chen Wei Fu Changyou Zhan Zhenghong Yuan 

机构地区：[1]Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS),Research Unit of Cure of Chronic Hepatitis B Virus Infection(CAMS),Shanghai Frontiers Science Center of Pathogenic Microbes and Infection,School of Basic Medical Sciences,Shanghai Medical College,Fudan University,Shanghai,P.R.China [2]Department of Pharmacology,School of Basic Medical Sciences,Fudan University,Shanghai,P.R.China [3]Shanghai Engineering Research Center for Synthetic Immunology,Fudan University,Shanghai,P.R.China [4]Eye Institute and Department of Ophthamology,Eye and ENT Hospital,Fudan University,Shanghai,P.R.China [5]Pharmacy Department of Huashan Hospital,Fudan University,Shanghai,P.R.China [6]Institute of Pediatric Translational Medicine,Shanghai Institute for Pediatric Congenital Heart Disease,Shanghai Children’s Medical Center,School of Medicine,Shanghai Jiao Tong University,Shanghai,China [7]Shanghai Institute of Infectious Disease and Biosecurity,Shanghai,P.R.China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3063-3076,共14页信号转导与靶向治疗（英文）

基　　金：supported by the grants from the National Key R&D Program of China(2023YFC2308603,2022YFA1303600,and 2021YFC2300600);the CAMS Innovation Fund for Medical Sciences(2019-12M-5-040);the National Natural Science Foundation of China(82125035,91842309,and 82302505);the Shanghai Education Commission Major Project(2021-01-07-00-07-E00081);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01S131);the Shanghai Sailing Program(22YF1409200);the China Postdoctoral Science Foundation(2022M710744).

摘　　要：This study aimed to develop a pan-genotypic and multifunctional small interfering RNA(siRNA)against hepatitis B virus(HBV)with an efficient delivery system for treating chronic hepatitis B(CHB),and explore combined RNA interference(RNAi)and immune modulatory modalities for better viral control.Twenty synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and evaluated.The lipid nanoparticle(LNP)formulation was optimized by adopting HO-PEG_(2000)-DMG lipid and modifying the molar ratio of traditional polyethylene glycol(PEG)lipid in LNP prescriptions.The efficacy and safety of this formulation in delivering siHBV(tLNP/siHBV)along with the mouse IL-2(mIL-2)mRNA(tLNP/siHBVIL2)were evaluated in the rAAVHBV1.3 mouse model.A siRNA combination(terms“siHBV”)with a genotypic coverage of 98.55%was selected,chemically modified,and encapsulated within an optimized LNP(tLNP)of high efficacy and security to fabricate a therapeutic formulation for CHB.The results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA(up to 3log_(10)reduction;vs PBS)in dose-and time-dependent manners at single-dose or multi-dose frequencies,with satisfactory safety profiles.Further studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus,via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4^(+)and CD8^(+)T cell responses by expressed mIL-2 protein.By adopting tLNP as nucleic acid nanocarriers,the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV,thus offering a promising translational therapeutic strategy for treating CHB.

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分 类 号：R512.62[医药卫生—内科学]