Repeated AAV-mediated gene transfer by serotype switching enables long-lasting therapeutic levels of hUgt1a1 enzyme in a mouse model of Crigler-Najjar Syndrome Type I

Gene Ther. 2017 Oct;24(10):649-660. doi: 10.1038/gt.2017.75. Epub 2017 Aug 14.

Abstract

Adeno-associated virus (AAV) -mediated gene therapy is a promising strategy to treat liver-based monogenic diseases. However, two major obstacles limit its success: first, vector dilution in actively dividing cells, such as hepatocytes in neonates/children, due to the non-integrating nature of the vector; second, development of an immune response against the transgene and/or viral vector. Crigler-Najjar Syndrome Type I is a rare monogenic disease with neonatal onset, caused by mutations in the liver-specific UGT1 gene, with toxic accumulation of unconjugated bilirubin in plasma, tissues and brain. To establish an effective and long lasting cure, we applied AAV-mediated liver gene therapy to a relevant mouse model of the disease. Repeated gene transfer to adults by AAV-serotype switching, upon neonatal administration, resulted in lifelong correction of total bilirubin (TB) levels in both genders. In contrast, vector loss over time was observed after a single neonatal administration. Adult administration resulted in lifelong TB levels correction in male, but not female Ugt1-/- mice. Our findings demonstrate that neonatal AAV-mediated gene transfer to the liver supports a second transfer of the therapeutic vector, by preventing the induction of an immune response and supporting the possibility to improve AAV-therapeutic efficacy by repeated administration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bilirubin / metabolism
  • Brain / metabolism
  • Crigler-Najjar Syndrome / therapy*
  • Dependovirus / genetics*
  • Female
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Genetic Vectors / genetics
  • Glucuronosyltransferase / genetics*
  • Glucuronosyltransferase / metabolism
  • HEK293 Cells
  • Humans
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Serogroup

Substances

  • UGT1A1 enzyme
  • Glucuronosyltransferase
  • Bilirubin