Table 1.
Summary of preclinical and clinical trials of liver targeted gene therapy.
| Vector | Payload | Disorder | Preclinical Results/Clinical Trial Endpoints | Clinical Trial/Phase | References |
|---|---|---|---|---|---|
| Retroviral | Factor VIII | Hemophilia A | Physiologic FVIII levels (mice) | [6] | |
| Lentiviral | Factor IX | Hemophilia B | Supraphysiologic FIX levels (nonhuman primates) | [20] | |
| Lentiviral | Factor IX | Hemophilia B | Sustained FIX expression, prevention of NAb induction (mice) | [21] | |
| Lentiviral | CRISPR/Cas9 | Hepatitis B | Inhibition of HBV replication in vivo (mice) and in vitro | [22,23] | |
| Lentiviral | Factor IX | Hemophilia B | Ex vivo stem cell gene correction and autologous stem cell transplant | NCT03961243/Phase I | |
| Adenoviral | UGT1A1 | Crigler-Najjar type I | Correction of hyperbilirubinemia (rats) | [26] | |
| Adenoviral | Human aquaporin 1 | Estrogen-induced cholestasis | Lower serum bile salt concentration, improved biliary output (rats) | [27] | |
| Adenoviral | miR-221/222 | NASH | Decreased hepatic fibrosis (mice) | [28] | |
| HDAd/Sleeping Beauty | Factor IX | Hemophilia B | Stable FIX expression (dogs) | [39,40] | |
| HDAd | AGT | Primary hyperoxaluria 1 | Stable transgene expression, decreased hyperoxaluria (mice) | [41] | |
| HDAd | AAT | AAT deficiency | Stable AAT expression (nonhuman primates) | [32] | |
| AAV | Factor IX | Hemophilia B | FIX expression decreased by 92% following 2/3 hepatectomy (mice) | [48] | |
| AAV | Factor IX | Hemophilia B | Robust FIX expression levels (mice) | [49] | |
| AAV | Copper transporting ATPase 2 | Wilson’s disease | Normalized serum holoceruloplasmin levels and hepatic parenchymal copper levels (mice) | [58] | |
| AAV | Human porphobilinogen | Acute intermittent porphyria | Reduced frequency of biochemical attacks, degree of neuropathy (mice) | [59,60] | |
| AAV | Propionyl-CoA | Propionyl acidemia | Decreased serum toxin level (mice) | [61] | |
| AAV | Human methylmalonyl-CoA mutase | Methylmalonic acidemia | Correction of acidemia, prevention of murine neonatal lethality | [62] | |
| AAV | Phenylalanine hydroxylase | Phenylketonuria | Reduced serum phenylalanine levels (mice) | [63] | |
| AAV | Glucose-6-phosphatase | Glycogen storage disease type Ia | Stable G6P expression, correction of hypoglycemia, normalized hepatic glycogen and reduced hepatic steatosis (mice, dogs) | [64,65] | |
| AAV | ABCB4 | Progressive familial intrahepatic cholestasis 3 | Stable ABCB4 expression, reduced progression of liver fibrosis (mice) | [66] | |
| AAV | Factor VIII | Hemophilia A | Stable FVIII expression (dogs) | [67,68] | |
| AAV | Factor IX | Hemophilia B | Stable FIX expression | NCT00979238/Phase I | [69] |
| AAV | Factor VIII | Hemophilia A | Stable FVIII expression | NCT02576795/Phase I/II | [45] |
| AAV | Factor IX | Hemophilia B | Stable FIX expression | NCT02484092/Phase II | [70,71] |
| AAV | Porphobilinogen deaminase | Acute intermittent porphyria | Safety, not metabolic correction at doses tested, varied results | NCT02082860/Phase I | [72] |
| AAV | LDLR | Homozygous familial hypercholesterolemia | Improvement of lipid profile | NCT02651675/Phase I/II | |
| AAV | Padua variant factor IX | Hemophilia B | Supraphysiologic FIX expression level | NCT03569891/Phase III | |
| AAV | Fidanacogene elaparvovec (high activity factor IX) | Hemophilia B | Supraphysiologic FIX expression level | NCT03587116/Phase III | |
| AAV | GS010 (human wild-type ND4) | Leber hereditary optic neuropathy | Recovery of vision |
NCT02652780 NCT02652767 NCT03293524, all Phase III |
|
| AAV | LYS-SAF302 (N-sulfoglucosamine sulfohydrolase) | Mucopolysaccharidosis IIIA | Improvement or stabilization of neurodevelopmental state | NCT03612869/Phase III | |
| AAV | NSR-REP1 (REP1) | Choroideremia | Improvement in best corrected visual acuity | NCT03496012/Phase III | |
| AAV | Valoctocogene roxaparvovec (factor VIII) | Hemophilia A | Improvement in FVIII median activity |
NCT03370913 NCT03392974, both Phase III |
|
| AAV | Voretigene neparvovec-rzyl (RPE65) | Biallelic RPE65 mutation-associated retinal dystrophy | Improvement in multi-lumen mobility test scores | FDA approved | [73] |
| AAV | Onasemnogene abeparvovec-xioi (SMN) | Spinal muscular atrophy | Prevention of death and permanent breathing support | FDA approved | [74] |
| SV40 | UGT1A1 | Crigler-Najjar type I | Normalization of murine ALT and bilirubin serum levels, liver histology | [82] | |
| Sleeping Beauty | Factor VIII | Hemophilia A | Stable FVIII expression | [108,109,110] | |
| Sleeping Beauty | Factor IX | Hemophilia B | Stable FIX expression | [108,109,110] | |
| Sleeping Beauty | AAT | AAT deficiency | Stable AAT expression (mice) | [108,109,110] | |
| Sleeping Beauty | β-glucuronidase | Mucopolysaccharidosis type VII | Stable β-glucuronidase expression (mice) | [108,109,110] | |
| Sleeping Beauty | α-L-iduronidase | Mucopolysaccharidosis type I | Stable α-L-iduronidase expression (mice) | [108,109,110] | |
| Sleeping Beauty | Fah | Hereditary tyrosinemia | Stable Fah expression (mice) | [108,109,110] | |
| Sleeping Beauty | LDLR, VLDLR | Familial hypercholesterolemia | Moderate reduction in plasma cholesterol and atherosclerosis (mice) | [111] | |
| Sleeping Beauty | von Willebrand factor | von Willebrand disease | Supraphysiologic VFW levels (mice) | [112] | |
| piggyBac | Factor VIII | Hemophilia A | Stable FVIII expression | [119] | |
| piggyBac | Factor IX | Hemophilia B | Stable FIX expression | [120] | |
| Non-viral (trivalent N-acetylgalactosamine) | Givosiran (siRNA) | Acute intermittent porphyria | Silences δ-aminolevulinic acid synthase 1 mRNA, reduces AIP attack frequency | FDA approved | [138] |
| Non-viral (liposomes) | Patisiran (siRNA) | Transthyretin-related hereditary amyloidosis | Improvement in polyneuropathy | FDA approved | [139] |
| Non-viral (trivalent N-acetylgalactosamine) | Lumasiran (siRNA) | Primary hyperoxaluria 1 | Decreased hyperoxaluria by silencing glycolate oxidase | NCT02706886/Phase I/II | [140] |
| Non-viral (trivalent N-acetylgalactosamine) | Fitusiran (siRNA) | Hemophilia A & B | Reduces bleeding instances by silencing antithrombin | NCT03417245/Phase III | [141] |
| Non-viral (trivalent N-acetylgalactosamine) | ALN-HBV02 (siRNA) | Hepatitis B | Reduction in HBV surface antigen levels | NCT02826018/Phase I | [142] |
| Non-viral (lipid nanoparticle) | Arginase 1 | Arginine deficiency | Stable, moderate arginase 1 expression (mice) | [143] | |
| Non-viral (SQ injection) | miR-122 antagomir | NASH | Improvement in hepatic steatosis and reduction in plasma cholesterol (mice) | [150] | |
| Non-viral (SQ injection) | miR-122 antagomir | Hepatitis C | Inhibition of viral replication and translation in vitro | [149,153] | |
| AAV | miR-26A | Hepatocellular carcinoma | Suppression of tumorigenesis and induction of tumor-specific apoptosis (mice) | [154] | |
| AAV | Factor VIII, ZFN | Hemophilia A | Stable expression of FVIII (mice) | [157] | |
| AAV | Factor IX, ZFN | Hemophilia B | Stable expression of FIX (mice) | [158,159] | |
| AAV | Human α-galactosidase A, ZFN | Fabry disease | Stable expression of α-galactosidase A (mice) | [159] | |
| AAV | Acid β-glucosidase, ZFN | Gaucher disease | Stable expression of acid β-glucosidase (mice) | [159] | |
| AAV | Iduronate-2 sulfatase, ZFN | Hunter syndrome | Stable expression of iduronate-2 sulfatase (mice) | [159] | |
| AAV | α-L-iduronidase, ZFN | Hurler syndrome | Stable expression of α-L-iduronidase (mice) | [159] | |
| Lentiviral | TALENs targeting diacylglycerol acyltransferase-1 | Hepatitis C | Viral entry impaired in a claudin-1 dependent manner in vitro | [161] | |
| Non-viral (ssDNA oligonucleotides) | Fah, CRISPR/Cas9 | Hereditary tyrosinemia | Correction of Fah mutation (mice) | [166] | |
| AAV | CRISPR/Cas9 | Induction of severe hypercholesterolemia and atherosclerosis | Via mutation of LDLR (mice) | [167] | |
| Adenoviral | AAT, CRISPR/Cas9 | AAT deficiency | Somatic murine hepatic incorporation and stable expression of AAT | [168] | |
| AAV | CRISPR/Cas9 | Hepatitis B | Inhibition of genome replication in mice | [173] | |
| Non-viral (DNA plasmids) | CRISPR/Cas9 | Induction of hepatocellular carcinoma | Via mutation of p53 and Pten (mice) | [176] | |
| None | Ex vivo PD-1 knockout in T lymphocytes engineered via CRISPR | Hepatocellular carcinoma | Tumor response rate, progression-free survival | NCT04417764 | |
| AAV | CRISPR/Cas9 | Phenylketonuria | Correction of PKU mutation via base editing (mice) | [179] |