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

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.