Table 2. Genome editing strategies applied to rare liver diseases.
| Pathology | OMIM | Inheritance | Prevalence | Clinical phenotype | Target gene | Gene editing approaches | Strategy | Model | References |
|---|---|---|---|---|---|---|---|---|---|
| Phenylketonuria (PKU) | 261600 | AR | 1:10,000–1:15,000 | Impaired cognitive development, seizures, autism, motor deficits, eczematous rashes | PAH | FokI-dCas9 system; CRISPR-Cas associated gene editors | HDR; base editing | COS-7 cells; Pahenu adult mouse | (15,17) |
| Ornithine transcarbamylase deficiency | 311250 | XLR | 1:70,000 | Vomiting, lethargy, ataxia, coma, seizures, cerebral edema, developmental delay, mental retardation | OTC | CRISPR/Cas9 | HDR | Spfash mouse | (20) |
| Arginase-1 deficiency | 207800 | AR | 1:1,100,000 | Slowing of growth, spasticity, loss of developmental milestones | ARG1 | CRISPR/Cas9; TALENs | HDR | Arg-1 deficient mouse | (25,26) |
| α-1 antitrypsin deficiency (AATD) | 613490 | AR | 1:5,000–1:7,000 (North America); 1:1,500-1:3,000 (Scandinavia) | Jaundice, hyperbilirubinemia, cirrhosis (rare) | SERPINA1 | ZFN-piggyBac transposon; CRISPR/Cas9; promoterless rAAV | HDR; NHEJ | iPSCs from patients; PiZ mouse; C57BL/6J mouse | (28-30,32-36) |
| Tyrosinemia type 1 (HTI) | 276700 | AR | 1/100,000 births | Progressive liver failure, renal tubular damage, porphyria like neurologic crisis, early development of hepatocellular carcinoma | FAH/HPD | Promoterless rAAV; CRISPR/Cas9; saCas9; Nme-Cas9; Cas9 nickases; CRISPR-Cas associated gene editors | HDR; microhomology-mediated end-joining; targeted sequence substitution; allelic exchange/NHEJ; base editing | fah-/- mice; fah-/- rats; Fahneo/PM mice; fah-/- primary hepatocytes; in utero | (41-55) |
| Mucopolysaccharidosis | 607014, 607015, 607016 (MPS1); 309900 (MPS2) | AR; XLR | MPS1: 1:100,000; MPS2: 1:100,000 males | Heterogeneous: skeletal and joint abnormalities, airway obstruction, hepatosplenomegaly. Neurocognitive impairment, cardiac abnormalities | IDUA; IDS | ZFNs; CRISPR/Cas9 | Targeted insertion in safe harbors; HDR; allelic exchange | IDSy/- KO mice; Fibroblasts from patients; iPSCs from idua KO mouse | (49,58-63) |
| Hemophilia A (HA)/Hemophilia B (HB) | 306700/306900 | XLR/ XLR | 1 in 5,000 males/1 in 30,000 males | Impaired hemostasis | F8/F9 | CRISPR/Cas9; TALENs; ZFNs; promoterless rAAV | Inversion flip-flop; HDR; targeted insertion in safe harbors | hiPSCs from patients; engineered hiPSCs; HA/CD4 null mice; HB mice; neonatal and adult hF9/HB mice; R333Q hemophilia mice | (58,67-80) |
| Hypercholesterolemia | NA | NA | – | High level of circulating concentration of low-density lipoprotein (LDL) cholesterol | PSK9 | CRISPR/Cas9: spCas9, saCas9, nmeCas9 Nme2Cas9; ZFNs; Meganucleases; CRISPR-Cas associated gene editors; dCas9-KRAB | NHEJ; silencing via base editing; transcription silencing | wild-type mice; FRG KO humanized mice; C57Bl/6 mice; macaques; in utero | (53,55,72,87-95) |
AR, autosomal recessive; XLR, X-linked recessive; NA, not applicable; ZFNs, zinc finger nucleases; TALENs, Transcription activator-like effector nucleases; CRISPR/Cas9, clustered regularly interspaced short palindromic repeat/(CRISPR)-associated nucleases 9; spCas9, Streptococcus pyogenes Cas9; saCas9: Staphylococcus aureus Cas9; NmeCas9, Neisseria meningitides Cas9; KRAB, Krüppel-associated box epigenetic repressor motif NHEJ, non-homologous end joining; HDR, homology directed repair; iPSCs, induced pluripotent stem cells.