Promoterless gene targeting without nucleases rescues lethality of a Crigler-Najjar syndrome mouse model.

Abstract

Crigler-Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduction in plasma bilirubin lasting for at least 12 months, the latest time point analyzed. Mutant mice, which expressed about 5-6% of WT Ugt1a1 levels, showed normal liver histology and motor-coordination abilities, suggesting no functional liver or brain abnormalities. These results proved that the promoterless gene therapy is applicable for CNSI, providing therapeutic levels of an intracellular ER membrane-bound enzyme responsible for a lethal liver metabolic disease.

• Authors: Fabiola Porro, Giulia Bortolussi, Adi Barzel, Alessia De Caneva, Alessandra Iaconcig, Simone Vodret, Lorena Zentilin, Mark A Kay, Andrés F Muro
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 9 Issue 10 Pg. 1346-1355 (10 2017) ISSN: 1757-4684 [Electronic] England
• PMID: 28751579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2017 International Centre for Genetic Engineering and Biotechnology Published under the terms of the CC BY 4.0 license.

Chemical References

• UGT1A1 enzyme
• Glucuronosyltransferase
• Bilirubin

Topics

• Animals
• Bilirubin (blood)
• Brain (pathology)
• Crigler-Najjar Syndrome (genetics, therapy)
• Disease Models, Animal
• Gene Targeting (methods)
• Genetic Therapy (methods)
• Glucuronosyltransferase (genetics, metabolism)
• Humans
• Hyperbilirubinemia (genetics, therapy)
• Liver (pathology)
• Mice
• Mice, Mutant Strains
• Promoter Regions, Genetic
• Survival Analysis
• Transduction, Genetic