Gene Replacement Therapy for Genetic Hepatocellular Jaundice

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.

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography

“…All subjects provided their written informed consent before the study. Six healthy male Japanese subjects and a patient with Dubin-Johnson syndrome (DJS) diagnosed based on the clinical features and serum bilirubin species (Dubin and Johnson, 1954;Lee et al, 2006;van Dijk et al, 2015) were enrolled in the study. The mean ages in the healthy subjects and the DJS patient were 32 6 9 and 67 years; the body weight and height in the healthy subjects were 65.3 6 8.7 kg and 166.8 6 6.1 cm, respectively, and that in the DJS patient were 59 kg and 158 cm, respectively.…”

Transplanted Human Pluripotent Stem Cell-Derived Mesenchymal Stem Cells Support Liver Regeneration in Gunn Rats

“…Phototherapy significantly influences patient's quality of life and can cause DNA damage [3]. Other treatment options such as liver transplantation, liver-directed gene therapy [4], and hepatocyte transplantation [5] require matching donors or involve suppression of the recipient's immune system. Thus, there is an urgent unmet need for alternative treatment options for Crigler-Najjar syndrome.…”

Liver‐targeted gene therapy: Approaches and challenges

“…39 Also, rAAV3 vectors were shown to reduce tumorigenesis in human liver cancer cells in vitro and in a mouse xenograft model of hepatocellular carcinoma (HCC). 40 Because of their excellent safety profile, rAAV vectors are being used widely in clinical trials, 26,41,42 even though their preclinical outcomes are not always predictable in humans. [43][44][45] To understand this problem, a study has been conducted with different variants of clinically relevant rAAV vectors in a human-mouse chimeric liver model.…”

“…Despite these issues, clinical trials in humans are being performed with rAAV vectors for a number of liver diseases. 42 The use of rAAV vectors has been demonstrated recently to inhibit miRNAs and liver-specific genes as well. In 1 study, specific and long-term inhibition of miR-NAs was achieved by the expression of "tough decoys" from rAAV9 vectors to study gene therapy for diseases caused by miRNA deregulation, such as dyslipidemia.…”

“…In fact, a number of gene therapy trials using viral and nonviral vectors targeting the liver are currently underway. 42 Up-todate information on these trials is available at http:// clinicaltrials.gov/ and http://www.abedia.com/wiley. Data from animal models suggest that several different gene replacement strategies may eventually yield long-term expression of transgenes at therapeutic levels and that in situ correction of gene defects in hepatocytes may eventually be a therapeutic option.…”