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.
Authors
- Yiting Hu
- John R. Counsell (ORCID: https://orcid.org/0000-0001-9208-101X)
- Julien Baruteau (ORCID: https://orcid.org/0000-0003-0582-540X)
- Sergi Castellano (ORCID: https://orcid.org/0000-0002-5819-4210)
- Wendy Heywood (ORCID: https://orcid.org/0000-0003-2106-8760)
- Loukia Touramanidou
- Simon N. Waddington (ORCID: https://orcid.org/0000-0003-4970-4730)
- Youssef Khalil (ORCID: https://orcid.org/0000-0001-9025-3017)
- Jemima J. Burden (ORCID: https://orcid.org/0000-0001-5894-7043)
- Rajvinder Karda (ORCID: https://orcid.org/0000-0001-9821-483X)
- Philippa B. Mills (ORCID: https://orcid.org/0000-0002-9704-1268)
- Giandomenico Turchiano (ORCID: https://orcid.org/0000-0001-9980-6810)
- Ivan Doykov (ORCID: https://orcid.org/0000-0003-4683-9306)
- Andrei Claudiu Cozmescu (ORCID: https://orcid.org/0000-0003-1775-0265)
- Sonam Gurung (ORCID: https://orcid.org/0000-0003-3271-5273)
- Dale Moulding (ORCID: https://orcid.org/0000-0002-1431-7047)
- Paul Gissen (ORCID: https://orcid.org/0000-0002-9712-6122)
- Sian Goldsworthy (ORCID: https://orcid.org/0000-0002-9189-5617)
- Neil Sebire
- Mina Nazari
- Peter Clayton
- Dany Perocheau
Institutions
- Great Ormond Street Hospital (GB)
- Great Ormond Street Hospital for Children NHS Foundation Trust (GB)
- The Royal Free Hospital (GB)
- MRC Laboratory for Molecular Cell Biology (GB)
- UCL Biomedical Research Centre (GB)
- NIHR Great Ormond Street Hospital Biomedical Research Centre (GB)
- University College London (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-06-19
- DOI
- https://doi.org/10.1038/s41467-026-73631-x
- Primary Topic
- Virus-based gene therapy research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Great Ormond Street Hospital Charity
- Medical Research Council