Gene replacement therapy for genetic hepatocellular jaundice

Area of Science:

• Hepatology
• Medical Genetics
• Biochemistry

Background:

• Jaundice arises from bilirubin accumulation due to inherited defects in liver metabolism and transport.
• Rotor and Dubin-Johnson syndromes involve impaired bilirubin uptake or excretion.
• Gilbert and Crigler-Najjar syndromes stem from UGT1A1 enzyme deficiencies, affecting bilirubin conjugation.

Purpose of the Study:

• To review the clinical, pathophysiological, and genetic aspects of inherited bilirubin metabolism disorders.
• To discuss current and emerging therapeutic strategies, including viral gene therapy for Crigler-Najjar syndrome.

Main Methods:

• Literature review of inherited disorders of bilirubin metabolism and transport.
• Analysis of clinical features, genetic basis, and pathophysiology.
• Evaluation of existing and novel treatment modalities.

Main Results:

• Rotor syndrome: impaired bilirubin (re)uptake due to OATP1B1/OATP1B3 deficiency.
• Dubin-Johnson syndrome: defective conjugated bilirubin excretion due to MRP2 defect.
• Gilbert syndrome: mild unconjugated hyperbilirubinaemia from reduced UGT1A1 promoter activity.
• Crigler-Najjar syndrome: severe unconjugated hyperbilirubinaemia from UGT1A1 mutations, potentially lethal without treatment.

Conclusions:

• Inherited bilirubin transport and metabolism disorders present with varying degrees of hyperbilirubinaemia.
• Current treatments for severe forms like Crigler-Najjar syndrome have limitations.
• Viral gene therapy offers a potential new therapeutic avenue for genetic bilirubin disorders, with considerations for immunological effects.