Investigational AAV8 Gene Therapy GNT0003 Shows Safety in Crigler–Najjar Syndrome


In a small study, administration of the Généthon therapy encoding UGT1A1 resulted in no serious adverse events. It is also being evaluated in a larger pivotal trial.

Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy

Lorenzo D’Antiga, MD

A small cohort of patients with Crigler–Najjar syndrome who were being treated with phototherapy who were administered Généthon’s investigational gene therapy, an adeno-associated virus serotype 8 vector encoding UGT1A1 called GNT0003, have reported no serious adverse events (AEs) in a phase 1/2 study (NCT03466463) assessing the therapy’s safety.1

All told, the patients with the rare liver disease who received the higher dose (n = 3; 5×1012 vg/kg) had a decrease in bilirubin levels and were not receiving phototherapy at least 78 weeks after vector administration. The remaining patients in the study who received a single infusion of the gene construct (n =2) received a dose of 2×1012 vg/kg. The study’s primary end point was safety and efficacy, with the latter defined as serum bilirubin level of 300 μmol/L or lower at 17 weeks, 1 week after discontinuation of phototherapy.

“If the results of the pivotal part confirm the efficacy of our gene therapy for Crigler-Najjar syndrome, we will be able to move on to a product license application, making the treatment available to patients and providing them with significantly improved quality of life,” Frederic Revah, CEO of Genethon, said in a statement.2

“Although our study is small, among the patients who received the dose of 5×1012 vg/kg, GNT0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment. A test of replication in a larger, well-characterized cohort of patients will be important,” study author Lorenzo D’Antiga, MD, of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, in Bergamo, Italy, and colleagues wrote.1

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Crigler–Najjar Syndrome

Crigler–Najjar Syndrome Type I
A rare autosomal recessive disorder resulting from mutations in the UGT1A1 gene, leading to deficient hepatic bilirubin glucuronidation. This results in severe unconjugated hyperbilirubinemia due to the absence or minimal activity of the bilirubin uridine diphosphate glucuronosyltransferase (UGT) enzyme.
Clinical Manifestations
Individuals with Crigler–Najjar syndrome type I typically present with early-onset jaundice and rapidly progress to kernicterus, a severe neurological condition caused by bilirubin deposition in the brain. Neurological deficits include athetosis, choreoathetosis, and sensorineural hearing loss.
Treatment Challenges
Phototherapy remains the primary treatment, aimed at converting unconjugated bilirubin into water-soluble isomers that can be excreted. Although, because of inadequate UGT activity, phototherapy often provides limited efficacy. Liver transplantation is considered curative, though the availability of suitable donors poses a challenge.
Crigler–Najjar Syndrome Type II
A milder form, type II is characterized by partial UGT deficiency, resulting in moderate unconjugated hyperbilirubinemia. Unlike type I, kernicterus is not a concern, and affected individuals respond well to phenobarbital, which induces UGT expression and improves bilirubin metabolism.

In January 2023, the company announced that it had initiated a larger, pivotal trial in France, Italy, and the Netherlands to confirm the potential efficacy of the therapy in those aged 10 years and older.3 Revah said at the time that the company was “very pleased with this new step” as it hoped to “then move towards a registration application and the availability of the treatment for patients.”3

Regarding safety, there were no hypersensitivity reactions post infusion, and the mean total bilirubin level had decreased to 114±98 μmol/L at 16 weeks among the high-dose cohort. Alanine aminotransferase (ALT) level decreased from 58±14 IU/L at baseline to 17±4 IU/L at week 4, and stabilized within the normal range in all responders. By week 16, serum bilirubin levels in the low-dose group exceeded 300 μmol/L, and the high-dose group had bilirubin levels below 300 μmol/L in the absence of phototherapy at the end of follow-up (mean at baseline, 351±56 μmol/L; mean at final follow-up, 149±33 μmol/L).

"After hemophilia, Crigler-Najjar syndrome is the next liver disease treated by gene therapy. In this trial, we managed to restore the synthesis of a nonsecreted protein whose deficiency causes severe jaundice in affected patients,” D'Antiga said in a statement.2 Primary investigator Philippe Labrune, MD, also of the Department of Pediatric Hepatology, Gastroenterology, and Transplantation at Hospital Papa Giovanni XXIII, said, “I consider these first results to be exciting, encouraging, and even moving. We are confident the results of the pivotal part will confirm the efficacy of this gene therapy. Providing a treatment for Crigler-Najjar disease could be the beginning of new adventures for other hepatic metabolic diseases.”2

All told, the most common AEs reported were headache (overall events, n = 4; low dose, n = 2; high dose, n = 2) and alterations in liver-enzyme levels (overall events, n = 19; low dose, n = 11; high dose, n = 8). “Despite presenting with nearly normal liver architecture, most patients with the Crigler–Najjar syndrome have elevated liver enzyme levels at baseline (as was true of all the patients in this study),” D’Antiga et al noted, adding that this “did not appear to affect the safety or the efficacy of GNT0003: after vector administration, and concomitant with the decrease in bilirubin levels, liver-enzyme levels returned to normal. Our results suggest that GNT0003 restored UGT1A1 expression in hepatocytes and that it had a beneficial effect on the mild, ongoing liver disease that is typical of patients with the Crigler–Najjar syndrome.”

D’Antiga and colleagues additionally acknowledged that the lack of data on residual enzymatic activity was a limitation as the determination of disease severity was based on bilirubin levels— the investigators wrote that phenobarbital testing results would have been helpful in this context. Also, there were less-than-ideal details on the daily dose of phototherapy (“including hours of exposure, distance from the lamps, type and power of the bulbs, and extent of irradiance,” they wrote).

1. D’Antinga L, Beuers U, Ronzitti G, et al. Gene Therapy in Patients with the Crigler–Najjar Syndrome. N Engl J Med. 2023; 389:620-631. doi:10.1056/NEJMoa2214084
2. Positive Phase 1/2 Clinical Trial Results of Genethon’s Gene Therapy for Crigler-Najjar Syndrome, a Rare Liver Disease, Published in The New England Journal of Medicine. News release. Genethon. August 22, 2023. Accessed August 29, 2023.
3. Syndrome de Crigler-Najjar: Généthon a démarré la phase pivot de son essai de thérapie génique pour cette maladie rare du foie. News release. Généthon. January 9, 2023. Accessed August 29, 2023.
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