Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis

Bu, Fang-tian; Jia, Peng-cheng; Zhu, Yan; Yang, Yaru; Meng, Hongwu; Bi, Yihui; Huang, Cheng; Li, Jun

doi:10.1016/j.omtm.2022.06.009

Cited by 10 publications

(14 citation statements)

References 112 publications

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“…2C). This short durability of mRNA and protein expression currently presents a major challenge for mRNA LNP technology compared to AAV where greater transduction efficiency and long-term efficacy in mediating gene expression have been shown in several preclinical and clinical studies [23,28]. 1 mg/kg hABCB4 mRNA achieved a remarkable restoration of PC profile in bile to wild-type levels as measured by mass-spectrometry (Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Alsuraih

LaViolette

Lin

et al. 2023

Preprint

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Mutations in the ABCB4 gene lead to a wide-spectrum of rare liver diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3) and low-phospholipid associated cholelithiasis (LPAC) syndrome. PFIC3 patients develop symptoms during late infancy, including severe itching, jaundice, and failure to thrive. The condition may progress to liver failure during childhood or adulthood. This is a highly unmet medical condition where liver transplantation is the only option to correct this disease. Recently, exciting data suggested that restoration of the ABCB4 function via gene replacement could rescue liver phenotypes associated with ABCB4 dysfunction in a pre-clinical PFIC3 mouse model. Here, we used mRNA LNP platform to determine expression and durability of ABCB4 in the liver of wild-type mice. In addition, we generated Abcb4-/- mice to study the efficacy of systemic delivery of ABCB4 mRNA LNP. We observed a robust and durable expression of hABCB4 up to 72 hours post systemic dosing in the liver of wild-type mice. Systemic administration of hABCB4 mRNA achieved a remarkable restoration of phosphatidylcholine levels in bile, a significant decrease in liver stiffness as measured by shear wave elastography, and amelioration of liver histopathology including fibrosis and ductular reaction. We conclude that administration of hABCB4 mRNA LNPs was sufficient to ameliorate fibrosis markers in the PFIC3 mouse model. Our data suggests that gene replacement using mRNA LNP modality could provide an excellent opportunity for patients with biliary diseases.

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Section: Discussionmentioning

confidence: 99%

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Alsuraih

LaViolette

Lin

et al. 2023

Preprint

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“…Currently, growing evidence highlights AAV-dependent gene therapy has a promising therapeutic potential in various liver brosis animal models by correcting aberrantly dysregulated liver brosis-causing genes at the molecular level 35 . In this study, we used AAV6 carrying speci c shRNAs targeting HSC Thbs2 to examine whether and how THBS2 acts on liver brosis, since among the commonly used AAVs, only AAV6 shows a relevant myo broblast tropism 19 .…”

Section: Discussionmentioning

confidence: 99%

Hepatic stellate cell-derived thrombospondin-2 as a novel therapeutic target for liver fibrosis regardless of etiology

Zhang

et al. 2023

Preprint

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Thrombospondin-2 (THBS2) expression is closely associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has not been elucidated yet. Here we report THBS2 is predominantly expressed in activated HSCs and dynamically increases with liver fibrosis progression and decreased in regression. Selective interference of HSC Thbs2 evidently retards fibrosis progression and intrahepatic inflammatory infiltration in liver fibrosis mouse models. Mechanically, extracellular THBS2, as a dimer, specifically recognizes and directly binds to TLR4 receptor, activating HSCs via stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-β) pathways. Disruption of THBS2-TLR4-FAK/TGF-β signaling axis notably alleviates HSC activation and liver fibrosis aggravation. In conclusion, THBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-β signaling in an autocrine manner. Therapies targeting HSC Thbs2 via AAV6 vector-capsulated shRNA may represent a novel promising strategy to prevent or treat liver fibrosis.

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“…Hepatic fibrosis is a reaction of repeated prolongation of various chronic liver lesions, causing liver self-limiting healing ( 53 ), which can lead to the formation of cirrhosis. CD73, as the final rate-limiting enzyme produced by adenosine ( 25 ), has an important place in the process of liver fibrosis.…”

Section: Manuscript Formattingmentioning

confidence: 99%

CD73, a significant protein in liver diseases

et al. 2023

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Purine adenosine pathway exists widely in the body metabolism, and is involved in regulating various physiological processes. It is one of the important pathways of environmental regulation in human body. CD73 is essentially a protease that catalyzes further dephosphorylation of extracellular adenine nucleotides, hydrolyzing extracellular AMP to adenosine and phosphate. CD73 is an important part of the adenosine signaling pathway. Studies have shown that CD73-mediated adenosine pathway can convert the inflammatory ATP into the immunosuppressant adenosine. This paper aims to summarize the relevant effects of CD73 in the occurrence, development and prognosis of liver diseases such as viral hepatitis, highlight the important role of CD73 in liver diseases, especially in viral hepatitis such as HBV and HCV, and explore new clinical ideas for future treatment targets of liver diseases.

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Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis

Cited by 10 publications

References 112 publications

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Targeting ABCB4 using mRNA-LNP for the treatment of rare liver diseases

Hepatic stellate cell-derived thrombospondin-2 as a novel therapeutic target for liver fibrosis regardless of etiology

CD73, a significant protein in liver diseases

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