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Review
. 2022 Jun 22:26:191-206.
doi: 10.1016/j.omtm.2022.06.009. eCollection 2022 Sep 8.

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

Fang-Tian Bu  1   2 , Peng-Cheng Jia  1   2 , Yan Zhu  3 , Ya-Ru Yang  4 , Hong-Wu Meng  1   2 , Yi-Hui Bi  4 , Cheng Huang  1   2 , Jun Li  1   2
Affiliations
Review

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

Fang-Tian Bu et al. Mol Ther Methods Clin Dev. .

Abstract

Liver fibrosis is a wound-healing response that results from various chronic damages. If the causes of damage are not removed or effective treatments are not given in a timely manner, it will progress to cirrhosis, even liver cancer. Currently, there are no specific medical therapies for liver fibrosis. Adeno-associated virus (AAV)-mediated gene therapy, one of the frontiers of modern medicine, has gained more attention in many fields due to its high safety profile, low immunogenicity, long-term efficacy in mediating gene expression, and increasingly known tropism. Notably, increasing evidence suggests a promising therapeutic potential for AAV-mediated gene therapy in different liver fibrosis models, which helps to correct abnormally changed target genes in the process of fibrosis and improve liver fibrosis at the molecular level. Moreover, the addition of cell-specific promoters to the genome of recombinant AAV helps to limit gene expression in specific cells, thereby producing better therapeutic efficacy in liver fibrosis. However, animal models are considered to be powerless predictive of tissue tropism, immunogenicity, and genotoxic risks in humans. Thus, AAV-mediated gene therapy will face many challenges. This review systemically summarizes the recent advances of AAV-mediated gene therapy in liver fibrosis, especially focusing on cellular and molecular mechanisms of transferred genes, and presents prospective challenges.

Keywords: AAV; HSCs; cellular mechanism; gene therapy; liver fibrosis.

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Conflict of interest statement

The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Brief mechanistic concepts of liver fibrosis In response to chronic damage factors, hepatocytes produce a number of DAMPs or EVs that contain vital miRNAs, which can lead to the activation of macrophages or HSCs. A large number of pro-inflammatory and fibrogenic cytokines that are generated by activated macrophages also lead to the activation of HSCs. Activated HSCs start to proliferate and secrete pro-fibrogenic factors, leading to ECM deposition on the liver. Upon cessation of chronic injury, activated HSCs move toward inactivation and apoptosis, resulting in the regression of liver fibrosis. On the one hand, activated HSC is transformed into an inactive state under the action of inactivating factors, such as MMP2, MMP12, MMP13, TCF21, and PPAR-γ. On the other hand, under the action of activation of death receptor-mediated pathways and pro-apoptotic factors, such as FAS, TRAIL, caspase3, caspase8, and Bax, or the decline of pro-survival genes, such as TIMP1 and TGF-β1, activated HSCs turn to an apoptotic state.
Figure 2
Figure 2
Process of AAV-mediated gene vector transduction In liver fibrosis, AAV-mediated genes, miRNA, miRNA TuDs, circRNA, or shRNA are taken into the endosome within liver cells by endocytosis. Once they enter the nucleus, AAVs uncoat and release their single-stranded genome (ssDNA), which subsequently is converted into a double-stranded DNA (dsDNA) template; thus, the transgenic gene can be transcribed and translated from the template.
Figure 3
Figure 3
Different cellular and molecular mechanisms of AAV-mediated transgene expression in liver fibrosis AAV-mediated gene overexpression or silence targets different cellular and molecular mechanisms, including promoting proliferation of hepatocytes, apoptosis and inactivation of HSCs, and expansion of liver progenitor cells (LPCs), inhibiting hepatocyte injury and steatosis, macrophage-mediated inflammatory response, endothelial-mediated sinusoid capillarization, activation and proliferation of HSCs, EMT of cholangiocytes, or reprogramming aHSC/MF into hepatocyte-like cells.
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