GNT0003 restores gene expression in Crigler Najjar syndrome

A single, intravenous infusion of GNT0003, an adeno-associated virus vector serotype 8, restored gene expression among patients with Crigler Najjar syndrome, according to a late breaker presentation at the International Liver Congress.

“Crigler Najjar syndrome is a rare, inherited disorder of bilirubin metabolism due to mutations in uridine diphospho-glucuronate glucuronosyltransferase 1A1 (UGT1A1) causing deficit of UGT1A1 protein that conjugates bilirubin; if left untreated, this condition leads to severe neurological injury,” Lorenzo D’Antiga, MD, Pappa Giovanni XXIII Hospital, said. “Overnight phototherapy, up to 12 hours per day, can control the levels of bilirubin but it tends to lose efficacy over time. The only curative option for this condition is liver transplantation.”

In a multicenter, phase 2/3, open-label, dose escalation trial, researchers aimed to investigate the safety and efficacy of GNT0003 in encoding the UGT1A1 transgene under the control of a hepatocyte-specific promoter to allow for the long-term withdrawal of daily phototherapy. They enrolled 4 female patients with severe Crigler Najjar undergoing phototherapy ( 6 hours/day) and dosed them with increasing vector doses; half of the patients (aged 23 years and 26 years) received 2x10¹² vector genomes (vg)/kg (cohort 1) while the other half (aged 26 years and 18 years) received 5x10¹² vg/kg (cohort 2). Efficacy in this trial was defined as stable bilirubin levels < 300 µmol/L 1-week after phototherapy suspension.

According to preliminary data, patients in cohort 1 experienced a marked reduction in bilirubin at week 6 which lost efficacy by week 16. Compared with pretreatment bilirubin levels among patients in cohort 2 (282 µmol/L and 350 µmol/L), researchers noted bilirubin levels of 126 µmol/L and 89 µmol/L at week 1 and levels of 73 µmol/L and 57 µmol/L at week 4. One patient withdrew phototherapy at week 16 with a bilirubin level of 63 µmol/L at week 17; bilirubin remained stable 6 weeks after complete phototherapy withdrawal. There were no GNT0003-related serious adverse events and only one patient experienced vector-related adverse events.

“In patients with Crigler Najjar syndrome, GNT0003 was safe and well tolerated; GNT0003 at the dose of 5x10¹² vg/kg restored UGT1A expression to levels allowing safe phototherapy withdrawal,” D’Antiga said. “Long-term follow-up is planned to evaluate the persistence of UGT1A over time. Gene therapy is a promising treatment for patients with Crigler Najjar syndrome, potentially replacing liver transplantation.”