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Safety and efficacy analysis of in vivo lentiviral gene therapy in pre-clinical ARC syndrome models

ABSTRACT: Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a rare inherited disorder caused by defects in the VPS33B trafficking protein, leading to impaired bile flow, progressive liver disease and early death. No effective treatments are currently available. Gene therapy offers a potential approach by restoring the missing VPS33B protein in liver cells. Here, we show that liver-targeted lentiviral gene therapy safely and effectively rescues key features of ARC syndrome in a mouse model following in vivo administration by intravenous injection, combined with transient liver macrophage depletion. To assess the treatment efficacy, disease severity is exacerbated by 0.25% cholic acid diet feeds. A liver-specific vector shows a favourable safety profile over a ubiquitous vector. Mice receiving the safe liver-specific vector display improved survival, growth and liver function, reduced fibrosis and bile canaliculi restoration. These findings support targeted gene therapy as a promising treatment for ARC syndrome and related early-onset liver diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE329589 | GEO | 2026/05/06

REPOSITORIES: GEO

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Quantification of Human VPS33B expression in mouse liver via lentiviral transfection

Project description:Arthrogryposis, Renal dysfunction and Cholestasis (ARC) syndrome is a lethal autosomal recessive disorder caused by deficiencies of VPS33B or VIPAS39 trafficking proteins. VPS33B deficiency in hepatocytes disrupts bile secretion, leading to progressive liver fibrosis, terminal liver disease and death of most ARC patients before the age of one year. Here, we developed a lentiviral gene therapy for ARC syndrome. Therapeutic vectors EF1-VPS (ubiquitous), LP1-VPS (liver-specific) and GFP controls were produced and tested in vitro in HepG2 VPS33B-/- cells. In vivo safety was assessed using neonatal heterozygous Vps33bLiver+/- mice. For efficacy experiments, Vps33bLiver-/- mice received neonatal intravenous injections combined with transient liver macrophage depletion and cholestasis was exacerbated using a 0.25% cholic acid diet. EF1-VPS and EF1-GFP vectors raised safety concerns, with 3 in 10 treated mice developing hepatocellular carcinomas, compared to none treated with the liver-specific vectors. Integration site analysis evidenced clonal expansion and Tox as a common vector integration locus in the 3 carcinomas. The safe LP1-VPS vector showed efficacy through significant improvement in survival, growth, and ARC-specific biomarkers. Microscopy liver analysis displayed reduced fibrosis and restoration of bile canalicular ultrastructure. These findings offer hope for ARC syndrome patients and serve as proof-of-concept for lentiviral gene therapy safety and efficacy studies in early-onset liver disorders.[

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