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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.
The pathogenesis of liver fibrosis is relatively complex and may be the result of communication between various cells in the liver. Briefly, in response to chronic injury and pro-fibrogenic factors, hepatocytes produce a group of damage-associated molecular patterns (DAMPs) and vesicles containing vital microRNAs (miRNAs), which can promote the increased number of pro-inflammatory phenotypes of macrophages.
Fig. 2 Brief mechanistic concepts of liver fibrosis.
The composition of AAV is very simple, consisting of an icosahedral capsid with a diameter of ∼26 nm and a single-stranded DNA (ssDNA) genome of ∼4.7 kb. Two indispensable coding sections, Replication (Rep) and Capsid (Cap), are included in the genome of AAV, which is flanked by 145-bp inverted terminal repeats (ITRs) on each side. The Rep gene encodes four proteins, Rep40, Rep52, Rep68, and Rep78, that are involved in the replication and packaging of AAV, while the Cap gene encodes three proteins, VP1, VP2, and VP3, that form the 60-mer capsid in a ratio of 1:1:10, respectively. The capsids determine the range of the infected host by interacting with receptors and co-receptors on the cell surface.
Thus far, there are 12 natural AAV serotypes and 108 isolates (serovars) have been discovered and classified according to phylogenetic analyses. Generally speaking, different capsids of AAV have different binding receptors, tissue tropisms, and transduction efficiency. Notably, several AAV serotypes have been applied to different clinical trials, including AAV1, AAV2, AAV5, AAV6, AAV8, AAV9, and AAVrh10 (isolation from rhesus monkeys). It is worth mentioning that clinical trials of AAV-mediated gene therapy for liver-based metabolic and genetic diseases have increasingly been performed or are ongoing at the moment, and have achieved promising results. For example, scAAV8 encoding human plasma factor IX in rhesus macaques by intravenous injection showed a good tropism to liver and was sufficient for phenotypic correction in hemophilia.
Table 1The applications of different AAV serotype-mediated gene therapy in rodent liver fibrosis or cirrhosis.
| Serotypes and genes | Cell-specific promoter | OE/KD | Animal strains | Causes |
|---|---|---|---|---|
| AAV1 | ||||
| IGF-I | - | OE | SD rats | CCl4 i.g. |
| AAV2 | ||||
| HO-1 | - | OE | LEW rat | CCl4 i.g. |
| BMP7 | - | OE | BALB/c | CCl4 i.p. |
| miR-19b | collagen alpha 1 | OE | SD rats | BDL |
| AAV5 | ||||
| HGF | - | OE | BALB/c | CCl4 i.g.; BDL |
| AAV6 | ||||
| Tcf21 | - | OE | C57BL/6 | CCl4 i.p. |
| 6TFs | - | OE | C57BL/6 | CCl4 i.p. |
| Nestin | - | KD | C57BL/6 | CCl4 i.p.; DDC diet |
| AAV8 | ||||
| GNMT | - | OE | BALB/c; C57BL/6 | CCl4 i.p. |
| PHP14 | - | KD | C57BL/6 | CCl4 i.p. |
| ACE2 | - | OE | C57BL/6 | CCl4 i.p.; BDL; MCD diet |
| FOXA2 | TBG | OE | C57BL/6 | CCl4 i.p. |
| miR-29a | OE | C57BL/6 | CCl4 i.p. | |
| miR-221-3p | Ttr | KD | BALB/c | CCl4 i.p.; DDC diet |
| NRF2 | TBG | OE | C57BL/6 | HFD + AGEs |
| RCAN1.4 | - | OE | C57BL/6 | CCl4 i.p. |
| miR-21 | - | OE | C57BL/6 | schistosomiasis |
| miR-351 | - | KD | BALB/c | schistosomiasis |
| GDF11 | - | OE | BALB/c | CCl4 i.p; DDC diet |
| AAV9 | ||||
| PSTPIP2 | - | OE | C57BL/6 | CCl4 i.p. |
| SUN2 | - | OE | C57BL/6 | CCl4 i.p. |
| circFBXW4 | - | OE | C57BL/6 | CCl4 i.p. |
| TGF-β1 | GFAP | KD | SD Rat | DEN i.p. |
| LECT2 | - | KD | C57BL/6 | CCl4 i.p. |
In recent years, AAV-mediated gene delivery has been applied for the overexpression and knockdown of some important genes or non-coding RNAs in liver fibrosis, contributing to studying the vital molecular and cellular mechanism of transferred genes more conveniently. Here, we review the different cellular and molecular mechanisms of AAV-mediated gene therapy in liver fibrosis.
Fig. 3 Different cellular and molecular mechanisms of AAV-mediated transgene expression in liver fibrosis.
The safety, efficacy, and sustained transgene expression of AAV-mediated gene therapy have been confirmed in different liver fibrosis models, which encourages the exploration of therapeutic strategies that could focus on AAV-mediated gene delivery systems in the future. However, the present studies only exist at the animal level, and there is no representative clinical trial of AAV-mediated gene therapy for the treatment of liver fibrosis. Thus, the paucity of human data makes AAV-mediated gene therapy a great challenge, and there is still a long way to go before it can be used for human liver fibrosis.
Reference
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