top of page


Safety and efficacy analysis of in vivo lentiviral gene therapy for ARC syndrome

A C Cozmescu(1,2) L Touramanidou(1) M Nazari(1) S Gurung(1) D Perocheau(1) Y T Hu(1) J R Counsell(3) R Karda(4) S N Waddington(4) J Baruteau(1,2,5) G Turchiano(1) P Gissen(1,2,5)

1:Great Ormond Street Institute of Child Health, University College London, London, UK; 2:NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK; 3:Research Department of Targeted Intervention, UCL Division of Surgery and Interventional Science, London, UK; 4:EGA Institute for Women's Health, University College London, London, UK; 5:Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a severe autosomal recessive multi-system disorder resulting from mutations in VPS33B. The hepatocyte VPS33B deficiency results in abnormal bile secretion leading to progressive liver fibrosis. Research utilizing animal models indicates that lentiviral vectors (LV) may offer a safe option for in vivo gene therapy applications and can facilitate sustained transgene expression. We aimed to develop LV based gene therapy to treat ARC syndrome. To test the safety of this approach two LV vectors were tested in heterozygous Vps33b+/- knockout mice that do not show ARC phenotype: 1)  LV.EFS1α.coVPS33B vector expressed in multiple tissues, utilising ubiquitous (EFS1α) promoter and 2) LV.LP1.coVPS33B liver specific, using the LP1 promoter. The neonatally treated mice were analysed at 9 months. We observed an increased incidence of hepatocellular carcinoma (3:10) in LV.EFS1α.coVPS33B treated mice compared to (0:10) cases observed in mice treated with the LP1 containing vectors. Integration site analysis from tumour samples revealed a decreased Shannon diversity score and a low integration site diversity. Given LV.LP1.coVPS33B treatments proved safe, we further investigated their efficacy in treating the ARC liver phenotype when administered to neonate Vps33b-/- knockout mice. The therapeutic effect has been assessed at 12 weeks after the mice were being fed for 8 weeks an 0.25% cholic acid diet. The results have shown normalisation to wild-type values of blood parameters of liver toxicity as well as animal survival and growth.  These results bring hope to ARC syndrome patients and highlight the importance of safety screening for newly developed LVs.

bottom of page