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Gene Replacement Therapy for Genetic Hepatocellular Jaundice

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Abstract

Jaundice results from the systemic accumulation of bilirubin, the final product of the catabolism of haem. Inherited liver disorders of bilirubin metabolism and transport can result in reduced hepatic uptake, conjugation or biliary secretion of bilirubin. In patients with Rotor syndrome, bilirubin (re)uptake is impaired due to the deficiency of two basolateral/sinusoidal hepatocellular membrane proteins, organic anion-transporting polypeptide 1B1 (OATP1B1) and OATP1B3. Dubin-Johnson syndrome is caused by a defect in the ATP-dependent canalicular transporter, multidrug resistance-associated protein 2 (MRP2), which mediates the export of conjugated bilirubin into bile. Both disorders are benign and not progressive and are characterised by elevated serum levels of mainly conjugated bilirubin. Uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) is responsible for the glucuronidation of bilirubin; deficiency of this enzyme results in unconjugated hyperbilirubinaemia. Gilbert syndrome is the mild and benign form of inherited unconjugated hyperbilirubinaemia and is mostly caused by reduced promoter activity of the UGT1A1 gene. Crigler-Najjar syndrome is the severe inherited form of unconjugated hyperbilirubinaemia due to mutations in the UGT1A1 gene, which can cause kernicterus early in life and can be even lethal when left untreated. Due to major disadvantages of the current standard treatments for Crigler-Najjar syndrome, phototherapy and liver transplantation, new effective therapeutic strategies are under development. Here, we review the clinical features, pathophysiology and genetic background of these inherited disorders of bilirubin metabolism and transport. We also discuss the upcoming treatment option of viral gene therapy for genetic disorders such as Crigler-Najjar syndrome and the possible immunological consequences of this therapy.

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Abbreviations

aAbs:

Autoantibodies

AAV:

Adeno-associated virus

AIH:

Autoimmune hepatitis

CN:

Crigler-Najjar syndrome

EPO:

Erythropoietin

GS:

Gilbert syndrome

HSC:

Haematopoietic stem cells

LKM3:

Liver-kidney-microsomal antibodies 3

MRP2:

Multidrug resistance-associated protein 2

OLT:

Orthotopic liver transplantation

RS:

Rotor syndrome

UCB:

Unconjugated bilirubin

UGT1A1:

Uridine diphospho-glucuronosyl transferase 1A1

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  1. Department of Gastroenterology and Hepatology, Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, S1-172, University of Amsterdam, Meibergdreef 69, 1105BK, Amsterdam, The Netherlands

    Remco van Dijk, Ulrich Beuers & Piter J. Bosma

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  1. Remco van Dijk
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van Dijk, R., Beuers, U. & Bosma, P.J. Gene Replacement Therapy for Genetic Hepatocellular Jaundice. Clinic Rev Allerg Immunol 48, 243–253 (2015). https://doi.org/10.1007/s12016-014-8454-7

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