The New England Journal of MedicineGene Therapy in Patients with the Crigler–Najjar Syndrome

Current treatments include daily phototherapy and liver transplantation.

Crigler–Najjar syndrome, a rare genetic disorder characterized by the absence of the enzyme UGT1A1, leads to severe jaundice and can be fatal. A recent phase 1–2 study has explored the potential of gene therapy using an adeno-associated virus vector encoding UGT1A1, offering a new therapeutic avenue for patients with this challenging condition.

• Study Design
  • Phase 1–2 dose-escalation study
  • Five patients with Crigler–Najjar syndrome treated with phototherapy
  • Single intravenous infusion of adeno-associated virus serotype 8 vector encoding UGT1A1 (GNT0003)
  • Two patients received 2×10¹² vg/kg, three received 5×10¹² vg/kg
  • Primary end points: safety and efficacy, with efficacy defined by serum bilirubin level of 300 μmol per liter or lower at 17 weeks
• Key Findings
  • No serious adverse events reported
  • Common adverse events: headache, alterations in liver-enzyme levels
  • Alanine aminotransferase increased in four patients, treated with glucocorticoids
  • Lower dose exceeded 300 μmol per liter bilirubin; higher dose led to levels below 300 μmol per liter without phototherapy (mean level at final follow-up: 149±33 μmol per liter)
• Conclusion
  • Gene therapy with GNT0003 was safe in this small study
  • Higher dose resulted in decreased bilirubin levels, with patients not receiving phototherapy at least 78 weeks after vector administration.

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Did You Know?
Crigler–Najjar syndrome is so rare that it affects approximately 1 in a million newborns, making traditional treatments like liver transplantation challenging.