TY - JOUR
T1 - Gene Therapy in Patients with the Crigler-Najjar Syndrome
AU - D'Antiga, Lorenzo
AU - Beuers, Ulrich
AU - Ronzitti, Giuseppe
AU - Brunetti-Pierri, Nicola
AU - Baumann, Ulrich
AU - di Giorgio, Angelo
AU - Aronson, Sem
AU - Hubert, Aurelie
AU - Romano, Roberta
AU - Junge, Norman
AU - Bosma, Piter
AU - Bortolussi, Giulia
AU - Muro, Andrés F.
AU - Soumoudronga, Ravaka F.
AU - Veron, Philippe
AU - Collaud, Fanny
AU - Knuchel-Legendre, Nathalie
AU - Labrune, Philippe
AU - Mingozzi, Federico
N1 - Funding Information: Supported by Genethon , the European Union Horizon 2020 plan (grant agreement 755225), and Telethon Foundation ETS. Publisher Copyright: © 2023 Massachusetts Medical Society.
PY - 2023/8/17
Y1 - 2023/8/17
N2 - Background: Patients 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. Methods: We 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. Results: No 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). Conclusions: No 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.
AB - Background: Patients 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. Methods: We 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. Results: No 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). Conclusions: No 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.
KW - Gastroenterology
KW - Gastroenterology General
KW - Genetics
KW - Genetics General
KW - Liver Disease
KW - Neurology/Neurosurgery
KW - Neurology/Neurosurgery General
UR - http://www.scopus.com/inward/record.url?scp=85168256520&partnerID=8YFLogxK
U2 - https://doi.org/10.1056/NEJMoa2214084
DO - https://doi.org/10.1056/NEJMoa2214084
M3 - Article
C2 - 37585628
SN - 0028-4793
VL - 389
SP - 620
EP - 631
JO - The New England journal of medicine
JF - The New England journal of medicine
IS - 7
ER -