OR15

3-year Follow-up of Crigler-Najjar Syndrome Patients Treated with AAV-based Gene Therapy in the GNT-012-CRIG Study 

L D'Antiga(1) A Di Giorgio(1) S Aronson(2) U Beuers(2) N Brunetti Pierri(3) R Romano(4) P Bosma(2) P Veron(5) F Collaud(5) G Ronzitti(5) PR Le Brun(5) N Guerchet(5) E Guemas(6) N Knuchel Legendre(5) B Beaurain(5) M Sanz(5) A Valent(5) J Gao-Desliens(5) G Perret(5) P Labrune(7)

1:ASST Papa Giovanni XXIII, Paediatric Hepatology, Gastroenterology and Transplantation; 2:Amsterdam University Medical Center, Department of Gastroenterology and Hepatology, Tytgat Institute; 3:Telethon Institute of Genetics and Medicine; 4:University of Naples Federico II, Department of Translational Medicine; 5:Genethon, Evry France; 6:Biossec SAS, Paris; 7:APHP. Hôpital Antoine Béclère, CRMR Maladies Héréditaires du Métabolisme Hépatique, Clamart, and Paris-Saclay University

Patients with Crigler–Najjar syndrome (CNS) lack the Uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), leading to severe hyperbilirubinemia that causes irreversible neurologic injury and death. Severe CNS requires prolonged daily phototherapy (PT). The only cure is liver transplantation. 

We report the 3-year follow-up data of the dose-escalation part of a phase I/II/III study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 (GNT0003) in CNS patients treated with ≥6 hours/day phototherapy. Five patients received a single infusion of GNT0003: two received 2×10¹² vg/kg, and three received 5×10¹² vg/kg. The primary endpoints were measures of safety and efficacy; efficacy was defined as a serum bilirubin level ≤ 300 μmol/L without PT from week 16. 

No serious adverse events related to GNT0003 were reported. Two patients receiving low dose of GNT0003 still require PT. Within week 48 after treatment, three patients on high dose could stop PT and had bilirubin levels below 300 μmol/L (mean [±SD] bilirubin at baseline, 301±43 μmol/L with PT; at week 48, 100±32 μmol/L without PT). Within month 36, two of the three high-dose patients still do not require PT, having bilirubin levels below 300µmol/L (199±30 μmol/L at month 36); the third stopped using phenobarbital at week 87 (pregnancy wish) and had to resume PT at week 107.  

GNT0003 treatment was safe and well tolerated. These data showed preliminary evidence of sustained clinical benefit up to 36 months. The high dose 5×10¹² vg/kg is currently evaluated in a pivotal trial.