Gene therapy improves bilirubin levels in Crigler-Najjar syndrome

1. In this randomized controlled trial, a high dose of GNT0003 gene therapy was associated with decreased serum bilirubin and need for phototherapy. 

2. The most common adverse events associated with GNT0003 were headache and liver enzyme elevations.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Crigler-Najjar syndrome is a rare recessive disorder resulting in loss of function of the uridine diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1) enzyme, which conjugates bilirubin and aids its elimination. Severe disease presentation includes jaundice, hyperbilirubinemia, and increased risk of neurotoxicity and death. Although prolonged daily phototherapy can transiently treat jaundice, liver transplantation is the only curative option. GNT0003 is an adeno-associated virus serotype 8 (AAV8) vector incorporating the UGT1A1 gene. This was an open-label study to assess the efficacy and safety of a single intravenous GNT0003 for patients with severe Crigler-Najjar syndrome who required daily phototherapy. Two patients received a low dose, and three received a high dose. By 16 weeks, the lower dose recipients had serum bilirubin exceeding 300mmol/L and required phototherapy. Those who received the higher dose had levels below this threshold and went without phototherapy for at least 78 weeks after initial treatment. There were no serious adverse events. The study sample was small and the follow-up period was limited. However, these results provided initial evidence of the efficacy of GNT0003 in reducing serum bilirubin among patients with severe Crigler-Najjar syndrome and eliminating the need for phototherapy.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: The current study reported from the dose-escalation portion of a trial to assessing a single-dose intravenous infusion of UGT1A1 among adult patients with severe Crigler-Najjar syndrome. Patients 18 years and above who were receiving daily phototherapy to maintain a bilirubin level below 300mmol/L were eligible for inclusion. Exclusion criteria included past liver transplants, detectable neutralizing antibodies against AAV8, or advanced liver fibrosis. All patients received an immunosuppressive regimen of sirolimus, single-dose intravenous methylprednisolone, and oral prednisone before and after the administration of the gene therapy to minimize an immune response and antibody formation against GNT0003. Five patients received GNT0003: two received a lower dose of 2×10¹² vector genomes (vg)/kg body weight, and three received a higher dose of 5×10¹² vg/kg. The primary efficacy outcome was serum bilirubin level ≤300mmol/L at 17 weeks, one week after discontinuation of phototherapy. The two patients who received the lower GNT0003 dose both had serum bilirubin returning to above 300mmol/L, necessitating the continuation of phototherapy. The three patients who received the higher dose had bilirubin levels below 300mmol/L through to week 78, without continuing phototherapy. Among these patients, the mean bilirubin level decreased from 351±56mmol/L at baseline to 149±33mmol/L by the end of follow-up. No serious adverse events occurred. All patients demonstrated complete clearance of the AAV8 vectors. In summary, these results provided initial evidence that GNT0003, at a high dose, resulted in successful gene transfer of UGT1A1 and sustained reduction of serum bilirubin among patients with severe Crigler-Najjar syndrome without the need for further phototherapy.

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