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Gene therapy for Crigler-Najjar syndrome appeared promising in patients treated at a higher dose, a phase I/II trial showed.

A single infusion of GNT0003 -- an adeno-associated virus serotype 8 vector carrying a correction for the genetic defect in the UGT1A1 gene that causes the toxic buildup of bilirubin that is the hallmark of the condition -- kept bilirubin levels below 300 μmol/L in the absence of phototherapy through roughly 18 months of follow-up in three trial participants who received a high dose.

Patients receiving 5×10¹² vector genomes (vg) per kg body weight had their bilirubin level drop from a mean of 351 μmol/L at baseline to 149 μmol/L at the final follow-up visit -- as low as 20% to 30% of baseline values, reported Lorenzo D'Antiga, MD, of Hospital Papa Giovanni XXIII in Bergamo, Italy, and colleagues in the .

Another two patients who received a lower dose of 2×10¹² vg/kg had a rise in serum bilirubin beyond that threshold by week 16, although no serious events were seen in either group from the treatment.

D'Antiga and team noted the need for better treatment options for these patients, as prolonged daily phototherapy only partially and transiently controls the jaundice, and allogeneic hepatocyte transplantation has had only limited and temporary effects. Patients only are cured from liver transplantation.

"Although our study is small, among the patients who received the dose of 5×10¹² vg per kilogram, GNT0003 restored UGT1A1 activity to levels that permitted suspension of phototherapy, and the efficacy persisted at 18 months after the treatment," the authors wrote. "A test of replication in a larger, well-characterized cohort of patients will be important."

A bilirubin level over 300 μmol/L can cause irreversible neurologic injury and death. In Crigler-Najjar syndrome, defective UGT1A1 gene variants produce little or none of an enzyme that the liver uses to conjugate bilirubin into a form that can be excreted. High levels of unconjugated bilirubin overwhelm the albumin that, in a healthy person, normally binds to it and carries it to the liver. This unconjugated, unbound form is fat-soluble and passes through the blood-brain barrier to interfere with neural tissue.

Crigler-Najjar syndrome is a recessively inherited metabolic disorder of the liver that affects 0.6 to 1 in 1 million newborns globally, which, while rare, still makes it one of the major causes of congenital non-hemolytic jaundice.

This study included five women ages 21 to 30 with severe Crigler-Najjar syndrome who were given the gene therapy in an open-label manner while maintaining their usual type, time, and mode of phototherapy before and after GNT0003 administration, along with other treatments, such as phenobarbital. Daily phototherapy used at least 6 hours overnight was tapered from week 14 to stop at week 16 before the endpoints were measured at week 17.

Gene therapy was given with a protocol of sirolimus in the weeks around gene therapy infusion (extended to 52 weeks in the protocol after the first three patients had recurrence of liver enzyme elevations after stopping), along with methylprednisolone on the day prior and prednisone in the weeks afterward. Supplementary prednisone could be given at the investigators' discretion in response to liver enzyme or bilirubin level changes suggesting a T-cell response against the vector or during sirolimus tapering.

However, no serious adverse events, hypersensitivity reactions, or cellular immune responses against the viral vector capsid were reported. The most common adverse events were headache and altered liver-enzyme levels.

"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 and colleagues wrote. "This did not appear to affect the safety or the efficacy of GNT0003."

Aminotransferase rose above the upper limit of the normal range in four patients, potentially due to an immune response against the infused vector. But with a course of glucocorticoids 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," the authors concluded.

At the end of the 48-week follow-up, patients were transitioned to a long-term follow-up study, with follow-up to week 78 for two of the high-dose patients and to week 80 for one.

Eligibility for the study was ruled out for patients with prior liver transplant, detectable serum neutralizing antibodies against the viral vector, or advanced liver fibrosis.

Much like hemophilia, for which gene therapy has succeeded in reducing bleeding, the researchers noted, "Crigler-Najjar syndrome is a candidate disease for gene-replacement therapies because it is a well-characterized monogenic disease and has a uniquely hepatic origin and because endpoints of efficacy are easy to measure."

"More generally, our findings support the possibility of long-term correction of a genetic disease caused by inactive variants in a gene that encodes a nonsecreted liver protein (UGT1A1 is a membrane-bound protein residing in the endoplasmic reticulum of hepatocytes)," they added.

In addition to larger studies, long-term transgene expression in the liver needs to be assessed, given that Crigler-Najjar syndrome arises in childhood, D'Antiga and team acknowledged.

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