Abstract
Crigler-Najjar (CN) syndrome is a recessive inherited disorder caused by deficiency of uridine diphosphoglucuronosyl transferase 1A1. This hepatic enzyme catalyzes the glucuronidation of bilirubin, an essential step in excretion into bile of this neurotoxic compound. As a result, CN patients suffer from severe unconjugated hyperbilirubinemia and are at risk of bilirubin encephalopathy. Over the last decades ex vivo and in vivo gene therapy using viral and nonviral vectors has been used to correct hyperbilirubinemia in the relevant animal model for CN syndrome, the Gunn rat. Several of these approaches did result in long-term correction of serum bilirubin levels in this animal model. However, none have been translated into a clinical trial. In this review we will recapitulate the strategies used and discuss their suitability for clinical application in the near future. We will also address specific safety measures in the gene therapy protocol needed to prevent adverse effects such as bilirubin toxicity. Since CN seems an ideal model for other monogenetic inherited metabolic liver disorders, development of liver-directed gene-therapy has relevance beyond this rare disease.
Keywords: Bilirubin, UGT1A1, Gunn rat, Adenovirus, Retrovirus, Lentivirus, AAV, Non-viral vectors
Current Gene Therapy
Title: Towards Liver-Directed Gene Therapy for Crigler-Najjar Syndrome
Volume: 9 Issue: 2
Author(s): Paula S. Montenegro Miranda and Piter J. Bosma
Affiliation:
Keywords: Bilirubin, UGT1A1, Gunn rat, Adenovirus, Retrovirus, Lentivirus, AAV, Non-viral vectors
Abstract: Crigler-Najjar (CN) syndrome is a recessive inherited disorder caused by deficiency of uridine diphosphoglucuronosyl transferase 1A1. This hepatic enzyme catalyzes the glucuronidation of bilirubin, an essential step in excretion into bile of this neurotoxic compound. As a result, CN patients suffer from severe unconjugated hyperbilirubinemia and are at risk of bilirubin encephalopathy. Over the last decades ex vivo and in vivo gene therapy using viral and nonviral vectors has been used to correct hyperbilirubinemia in the relevant animal model for CN syndrome, the Gunn rat. Several of these approaches did result in long-term correction of serum bilirubin levels in this animal model. However, none have been translated into a clinical trial. In this review we will recapitulate the strategies used and discuss their suitability for clinical application in the near future. We will also address specific safety measures in the gene therapy protocol needed to prevent adverse effects such as bilirubin toxicity. Since CN seems an ideal model for other monogenetic inherited metabolic liver disorders, development of liver-directed gene-therapy has relevance beyond this rare disease.
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Cite this article as:
Montenegro Miranda S. Paula and Bosma J. Piter, Towards Liver-Directed Gene Therapy for Crigler-Najjar Syndrome, Current Gene Therapy 2009; 9 (2) . https://dx.doi.org/10.2174/156652309787909508
DOI https://dx.doi.org/10.2174/156652309787909508 |
Print ISSN 1566-5232 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5631 |
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