Emerging therapeutic potential of adeno-associated virus-mediated gene therapy in liver fibrosis
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Updated: Sep 4, 2025
Efficient Gene Knockdown in the Liver via Intrasplenic Injection of Adeno-Associated Virus Serotype 8 (AAV8)-Delivered Small Hairpin RNA
Published on: November 1, 2024
Fang-Tian Bu1,2, Peng-Cheng Jia1,2, Yan Zhu3
1Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui Province 230032, China.
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.
Insights
Adeno-associated virus (AAV)-mediated gene therapy shows promise for treating liver fibrosis by correcting genes. However, challenges remain in predicting human safety and efficacy from animal models.
Area of Science:
- Hepatology
- Gene Therapy
- Molecular Medicine
Background:
- Liver fibrosis is a chronic liver condition with no current specific treatments, potentially progressing to cirrhosis and liver cancer.
- Adeno-associated virus (AAV)-mediated gene therapy offers a novel therapeutic avenue due to its safety, low immunogenicity, and sustained gene expression.
- Cell-specific promoters enhance AAV's therapeutic potential by targeting gene expression to specific liver cells.
Purpose of the Study:
- To review recent advancements in AAV-mediated gene therapy for liver fibrosis.
- To focus on the cellular and molecular mechanisms of gene transfer in liver fibrosis.
- To identify prospective challenges and limitations of AAV gene therapy in liver fibrosis.
Main Methods:
- Systematic review of current literature on AAV-mediated gene therapy for liver fibrosis.
- Analysis of cellular and molecular mechanisms underlying gene transfer and therapeutic effects.
- Evaluation of AAV tropism, immunogenicity, and genotoxic risks in preclinical models.
Main Results:
- AAV gene therapy demonstrates potential to correct aberrant genes involved in liver fibrosis at a molecular level.
- Targeted gene delivery using cell-specific promoters can improve therapeutic efficacy in liver fibrosis models.
- Preclinical animal models have limitations in predicting human tissue tropism, immunogenicity, and genotoxic risks.
Conclusions:
- AAV-mediated gene therapy is a promising strategy for liver fibrosis, offering molecular-level correction of disease processes.
- Further research is needed to overcome challenges related to human safety, efficacy, and translation from animal models.
- Optimizing AAV vectors and understanding human-specific responses are crucial for clinical application in liver fibrosis treatment.
