基因治疗克里格勒-纳贾尔综合征患者。

Gene Therapy in Patients with the Crigler-Najjar Syndrome.

机构信息

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.).

出版信息

N Engl J Med. 2023 Aug 17;389(7):620-631. doi: 10.1056/NEJMoa2214084.

DOI:10.1056/NEJMoa2214084

PMID:37585628

Abstract

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 2×10 vector genomes (vg) per kilogram of body weight, and three received 5×10 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. (Funded by Genethon and others; ClinicalTrials.gov number, NCT03466463.).

摘要

背景

克里格勒-纳贾尔综合征患者缺乏尿苷二磷酸葡萄糖醛酸基转移酶 1A1（UGT1A1）酶，这种酶的缺乏导致严重的未结合高胆红素血症，可导致不可逆转的神经损伤和死亡。长期、每日光疗部分控制黄疸，但唯一的根治方法是肝移植。

方法

我们报告了一项评估腺相关病毒血清型 8 载体编码 UGT1A1 基因单次静脉输注治疗接受光疗的克里格勒-纳贾尔综合征患者的安全性和疗效的 1 期-2 期研究剂量递增部分的结果。5 名患者接受了基因构建物（GNT0003）的单次输注：2 名患者接受每公斤体重 2×10 个载体基因组（vg），3 名患者接受每公斤体重 5×10 vg。主要终点是安全性和疗效指标；疗效定义为在停止光疗 1 周后 17 周时测量血清胆红素水平为 300 μmol/L 或更低。

结果

未报告严重不良事件。最常见的不良事件是头痛和肝酶水平改变。4 名患者的丙氨酸氨基转移酶升高至正常范围上限以上，这一发现可能与输注载体的免疫反应有关；这些患者接受了糖皮质激素治疗。到第 16 周，接受较低剂量 GNT0003 的患者的血清胆红素水平超过 300 μmol/L。接受较高剂量的患者在随访结束时（两名患者的最后随访时间为第 78 周，另一名患者为第 80 周），在没有光疗的情况下胆红素水平低于 300 μmol/L（平均[±SD]基线胆红素水平为 351±56 μmol/L；最终随访时的平均水平[周 78 在两名患者和周 80 在另一名患者]为 149±33 μmol/L）。