Table 2.
Gene therapy approaches for PFIC3.
| Aronson et al. [112] | Weber et al. [113] | Siew et al. [116] | Wei et al. [114] | |
|---|---|---|---|---|
| Strain Background | C57BL/6 Abcb4-/- | FVB Abcb4-/- | FVB Abcb4-/- | BALB/c Abcb4-/- |
| Phenotype | Mild (requiring cholate-enriched diet) |
Severe (similar to patients) |
Severe (similar to patients) |
More severe |
| Vector | AAV8 | AAV8 | Hybrid AAV-piggyBac transposon | LNP |
| Dose | 5 × 1013 vg/kg | 1 × 1014 vg/kg | ~2 × 1014 vg/kg | 1.0 mg/kg |
| Age of treatment | 10-week-old | 2- or 5-week-old | Newborn | 4-week-old |
| Outcomes | Increased biliary PC and cholesterol content. Rescue of serum ALT, ALP and bilirubin levels. Prevention of liver fibrosis. | Increased biliary PC. Rescue of serum transaminases, ALP and BA levels. Improvement of the degree of hepatosplenomegaly. Prevention and reversal of liver fibrosis. | Increased biliary PC. Decreased hepatomegaly and serum parameters (ALT, ALP, BAs). Reduced liver fibrosis and liver tumor incidence. | Increased biliary PC (10–25% WT) and %BW. Decreased hepatomegaly and serum parameters (ALT, ALP, BAs). Normalization of liver fibrosis and portal hypertension. |
| Advantages | Long-term correction. No risk of mutagenesis. | Granted orphan drug designation. Long-term prevention and correction at early and late stages of PFIC3, respectively. No risk of mutagenesis. | Long-term correction. Preventing genome loss by hepatocellular proliferation during liver growth. | No risk of mutagenesis. Less immune responses. |
| Disadvantages | Need for challenge with BA-enriched dietary supplementation (model). Need to evaluate efficacy in younger mice more representative of the age of patients. Risks of using a high viral dose. | Loss of long-term therapeutic effect in half of the females treated with a single dose. Need to address the immune response based on anti-AAV neutralizing antibody for repeated administrations of the vector. Risks of using a high viral dose. | Risk of mutagenesis. Transposase overexpression Lack of serotype that efficiently transduces human hepatocytes. |
Less durable expression. Requires repeated parenteral dosing. |
AAT, alpha-1 antitrypsin; AAV, adeno-associated vector; ALP, alkaline phosphatase; ALT, alanine aminotransferase; BW, body weight; LNP, lipid nanoparticles; LP1, liver-specific transcriptional control unit; PC, phosphatidylcholine; TRsh, short piggyBac terminal repeats; VG, viral genomes; WT, wild-type.