• Lorenzo D'Antiga, Ulrich Beuers, Giuseppe Ronzitti, Nicola Brunetti-Pierri, Ulrich Baumann, Angelo Di Giorgio, Sem Aronson, Aurelie Hubert, Roberta Romano, Norman Junge, Piter Bosma, Giulia Bortolussi, Andrés F Muro, Ravaka F Soumoudronga, Philippe Veron, Fanny Collaud, Nathalie Knuchel-Legendre, Philippe Labrune, and Federico Mingozzi.
• From Department of Pediatric Hepatology, Gastroenterology, and Transplantation, Hospital Papa Giovanni XXIII, Bergamo (L.D., A.D.G.), Scuola Superiore Meridionale, Genomics and Experimental Medicine Program (N.B.-P.), Department of Translational Medicine, University of Naples Federico II, Naples (N.B.-P., R.R.), Telethon Institute of Genetics and Medicine, Pozzuoli (N.B.-P.), and the International Center for Genetic Engineering and Biotechnology, Trieste (G.B., A.F.M.) - all in Italy; Tytgat Institute for Liver and Intestinal Research, Department of Hepatology and Gastroenterology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam (U. Beuers, S.A., P.B.); Université d'Evry, Université Paris-Saclay, INSERM, Genethon, Integrare Research Unit UMR_S951 (G.R., F.C., F.M.) and Genethon (G.R., R.F.S., P.V., F.C., N.K.-L., F.M.), Evry, Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Centre de Référence pour les Maladies Rares, Maladies Héréditaires du Métabolisme Hépatique, Hôpital Antoine Béclère, Clamart (A.H., P.L.), and Université Paris-Saclay and INSERM Unité 1195, Le Kremlin Bicêtre (A.H., P.L.) - all in France; the Division for Pediatric Gastroenterology and Hepatology, Department of Pediatric Kidney, Liver, and Metabolic Diseases, Hannover Medical School, Hannover, Germany (U. Baumann, N.J.); and Spark Therapeutics, Philadelphia (F.M.).
• N. Engl. J. Med. 2023 Aug 17; 389 (7): 620631620-631.

BackgroundPatients with the Crigler-Najjar syndrome lack the enzyme uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), the absence of which leads to severe unconjugated hyperbilirubinemia that can cause irreversible neurologic injury and death. Prolonged, daily phototherapy partially controls the jaundice, but the only definitive cure is liver transplantation.MethodsWe report the results of the dose-escalation portion of a phase 1-2 study evaluating the safety and efficacy of a single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 in patients with the Crigler-Najjar syndrome that was being treated with phototherapy. Five patients received a single infusion of the gene construct (GNT0003): two received 2×1012 vector genomes (vg) per kilogram of body weight, and three received 5×1012 vg per kilogram. The primary end points were measures of safety and efficacy; efficacy was defined as a serum bilirubin level of 300 μmol per liter or lower measured at 17 weeks, 1 week after discontinuation of phototherapy.ResultsNo serious adverse events were reported. The most common adverse events were headache and alterations in liver-enzyme levels. Alanine aminotransferase increased to levels above the upper limit of the normal range in four patients, a finding potentially related to an immune response against the infused vector; these patients were treated with a course of glucocorticoids. By week 16, serum bilirubin levels in patients who received the lower dose of GNT0003 exceeded 300 μmol per liter. The patients who received the higher dose had bilirubin levels below 300 μmol per liter in the absence of phototherapy at the end of follow-up (mean [±SD] baseline bilirubin level, 351±56 μmol per liter; mean level at the final follow-up visit [week 78 in two patients and week 80 in the other], 149±33 μmol per liter).ConclusionsNo serious adverse events were reported in patients treated with the gene-therapy vector GNT0003 in this small study. Patients who received the higher dose had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).Copyright © 2023 Massachusetts Medical Society.

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