Table 1.
CRISPR-based animal models of liver disorders.
| Disease | Model | Target | Tissue-specificity | Approach | Phenotype | Comments | Reference |
|---|---|---|---|---|---|---|---|
| Argininosuccinate lyase deficiency | Mouse | Asl, loss-of-function | Liver-targeted | SLiK | Hyperammonemia and somnolence | Pankowicz et al. 201830 | |
| Familial dysbetalipoproteinemia | Rat | Apoe, loss-of-function | None | Zygote injection; CRISPR/Cas9 | High level of circulating LDL-cholesterol, hypercholesterolemia, hepatosteatosis, atherosclerosis | Zhao et al., 201873 | |
| Familial hypercholesterolemia | Mouse, adult | Ldlr, loss-of-function | Liver-targeted | Intraperitoneal injection; AAV-CRISPR | High level of circulating LDL, hypercholesterolemia, atherosclerosis |
AAV vector integration at CRISPR/Cas9 cut sites | Jarrett et al., 201740 and Jarrett et al. 201871 |
| Rat | Ldlr, loss-of-function | None | Zygote injection; CRISPR/Cas9 | High level of circulating LDL-cholesterol, hypercholesterolemia, hepatosteatosis, atherosclerosis | Zhao et al., 201873 | ||
| Hereditary tyrosinemia type I | Rat | Fah, loss-of-function | None | Embryo injection; CRISPR/Cas9 | Hypertyrosinemia, liver fibrosis, cirrhosis | Zhang et al., 201658 | |
| Hypermanganesemia with dystonia, polycythemia, and cirrhosis | Zebrafish | slc30a10, loss-of-function | None | Embryo injection; CRISPR/Cas9 | High level of circulating and hepatic Mn, hepatosteatosis, liver fibrosis | Xia et al., 201764 | |
| Niemann-Pick disease type C1 | Zebrafish | npc-1, loss-of-function | None | Embryo injection; CRISPR/Cas9 | Hepatic accumulation of unesterified cholesterol | Tseng et al., 201865 Lin et al., 201866 |
|
| Wilson’s Disease | Rabbit | Atp7b, knock-in | None | Zygote injection; CRISPR/Cas9 | Accumulation of copper in liver and kidney |
High frequency of off-target editing was reported | Jiang et al., 201860 |
| Non-alcoholic fatty liver disease | Mouse, adult | Pten, loss-of-function | Liver-targeted | Hydrodynamic injection; CRISPR/Cas9 | Hepatomegaly, hepatosteatosis | Xue et al., 201447 | |
| Mouse, adult | Pten, loss-of-function | Liver-targeted | Tail vein injection; Ad-CRISPR/Cas9 | Hepatomegaly, hepatosteatosis, steatohepatitis (NASH-like) | Ad vector-associated immunotoxicity was observed in the liver | Wang et al., 201548 | |
| Rat, adult | Pten, loss-of-function | Liver-targeted | Hydrodynamic injection; CRISPR/Cas9 | Hepatosteatosis | High dosage of plasmid was required to induce NAFLD | Yu et al., 201749 | |
| Mouse | TM6SF2, loss-of function | None | Embryo injection; CRISPR/Cas9 | Decreased plasma total cholesterol and LDL |
No NAFLD phenotype | Fan et al. 201651 | |
| Progressive familial intrahepatic cholestasis type 2 | Zebrafish | abcb11b, loss-of-function | None | Embryo injection; CRISPR/Cas9 | Impaired bile excretion, hepatocellular injury, induction of autophagy in hepatocytes | Ellis et al., 201876 | |
| Mouse | Abcb11, loss-of-function | Liver-targeted | SLiK | Impaired bile excretion with increase of bile acid in serum | Pankowicz et al. 201830 | ||
| Hepatocellular carcinoma Intrahepatic cholangiocarcinoma |
Mouse, adult | Ten tumour suppressors, loss-of-function | Liver | HTVI, CRISPR-Cas9 vector flanked by SB repeats | Tumour growth | No off-target effects found by amplicon-based NGS | Weber et al., 201584 |
| Hepatocellular carcinoma | Mouse, adult | Nf1, Plxnb1, Flrt2, B9d1, loss-of-function | None | Subcutaneous transplantation of CRISPR/Cas9 edited p53-/-; Myc hepatoblasts (lentivirus) | Tumour growth | Song et al., 201787 | |
| Hepatocellular carcinoma | Mouse, adult | 56 known or putative tumour suppressors, loss-of-function | None | CRISPR AAV | Tumour growth | Wang et al., 201888 | |
| Hepatocellular carcinoma | Mouse, age uknown | Nras ,gain-of-function and Pten, loss-of-function | Liver | SB, CRISPR-Cas9, HTVI | Tumour growth, excessive lipid deposition in hepatocytes | Gao et al., 2017109 | |
| Hepatocellular carcinoma | Mouse, adult HBV transgenic mice | p53 and Pten, loss-of-function | Liver | CRISPR-Cas9, HTVI | Macroscopic tumour growth | Liu et al., 201793 | |
| Fibrolamellar hepatocellular carcinoma | Mouse, adult | Dnajb1-Prkaca gene fusion | Liver | CRISPR-Cas9, HTVI | Tumour growth | Engelholm et al., 201797 | |
| Fibrolamellar hepatocellular carcinoma | Mouse, adult | Dnajb1-Prkaca gene fusion | Liver | CRISPR-Cas9, HTVI | Tumour growth | Kastenhuber et al., 201796 | |
| Intrahepatic cholangiocarcinoma | Mouse, adult | p53 and Pten, loss-of-function | Liver | CRISPR-Cas9, HTVI, carbon tetrachloride | Tumour growth | Xue et al., 201447 | |
| Intrahepatic cholangiocarcinoma | Mouse, age unknown | HRASG12V gain-of-function, p53 loss-of-fucntion | Liver | HTVI; CRISPR homology-independent target integration | Tumour growth | Mou et al., 201991 |
AAV, adeno-associated viruses; HTVI, hydrodynamic tail vein injection; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NGS, next-generation sequencing; SLiK, somatic liver knockout.