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Liver-directed lentiviral gene therapy is safe and curative in Argininosuccinic aciduria

L Touramanidou(1) S Gurung(1) D P Perocheau(1) Y T Hu(5) S N Waddington(3) J R Counsell(6) A J Thrasher(5) P Gissen(1,2,4) G Turchiano(5) J Baruteau(1,2,4)

1:Great Ormond Street Institute of Child Health, University College London; 2:NIHR Great Ormond Street Hospital Biomedical Research Centre; 3:EGA Institute for Women's Health, University College London; 4:Metabolic Medicine, Great Ormond Street Hospital for Children NHS Foundation Trust; 5:Infection, Immunity and Inflammation Research and Teaching Department, Zayed Centre for Research into Rare Disease in Children, University College London; 6:Research Department of Targeted Intervention, UCL Division of Surgery and Interventional Science

The liver-based urea cycle enables nitrogen waste and clearance of neurotoxic ammonia. Argininosuccinic aciduria (ASA) caused by argininosuccinate lyase (ASL) deficiency is the second most common inherited urea cycle defect. Patients present either with neonatal- or late-onset hyperammonaemia, which causes coma and death if untreated, and a high risk of severe cognitive impairment and epilepsy. Curative liver transplantation can be performed in severe cases but requires lifetime immunosuppression. We aimed to test in vivo lentiviral gene therapy in neonatal ASL-deficient (AslNeo/Neo) mice. AslNeo/Neo animals received a neonatal intravenous injection of lentiviral vector at 4E10TU/kg encoding either the codon-optimised human ASL (LV.coASL) versus or a GFP as control. LV.coASL-injected animals survived for 12 weeks whilst control mice died within 4 weeks (p<0.001). Growth (p<0.01), fur coat pattern, ammonia (p<0.001), arginosuccinate (p<0.001), citrulline (p<0.01), and orotate (p<0.05) were normalised to those in wild-type mice. Significantly increased ASL expression (p<0.01) and activity (p<0.05) were observed in treated AslNeo/Neo livers compared to controls. Lentiviral vectors present long-term transgene expression due to their ability to integrate into the host genome. We conducted safety studies to address the presence of genotoxic events driven by the lentiviral vector in vivo. Twenty neonatal wild-type mice received LV.cohASL vector intravenously versus 20 PBS-injected littermates. Pathology and integration site analysis on livers at 9 months post injection confirmed absence of tumours and clonal dominance. Overall, those preliminary studies demonstrated proof of concept of in vivo lentiviral gene therapy for ASA and its safety profile.  

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