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Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer

Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is appli...

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Autores principales: Bortolussi, Giulia, Zentilin, Lorena, Baj, Gabriele, Giraudi, Pablo, Bellarosa, Cristina, Giacca, Mauro, Tiribelli, Claudio, Muro, Andrés F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Federation of American Societies for Experimental Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370676/
https://www.ncbi.nlm.nih.gov/pubmed/22094718
http://dx.doi.org/10.1096/fj.11-195461
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author Bortolussi, Giulia
Zentilin, Lorena
Baj, Gabriele
Giraudi, Pablo
Bellarosa, Cristina
Giacca, Mauro
Tiribelli, Claudio
Muro, Andrés F.
author_facet Bortolussi, Giulia
Zentilin, Lorena
Baj, Gabriele
Giraudi, Pablo
Bellarosa, Cristina
Giacca, Mauro
Tiribelli, Claudio
Muro, Andrés F.
author_sort Bortolussi, Giulia
collection PubMed
description Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination.—Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A. F. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer.
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spelling pubmed-33706762012-06-27 Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer Bortolussi, Giulia Zentilin, Lorena Baj, Gabriele Giraudi, Pablo Bellarosa, Cristina Giacca, Mauro Tiribelli, Claudio Muro, Andrés F. FASEB J Research Communications Crigler-Najjar type I (CNI) syndrome is a recessively inherited disorder characterized by severe unconjugated hyperbilirubinemia caused by uridine diphosphoglucuronosyltransferase 1A1 (UGT1A1) deficiency. The disease is lethal due to bilirubin-induced neurological damage unless phototherapy is applied from birth. However, treatment becomes less effective during growth, and liver transplantation is required. To investigate the pathophysiology of the disease and therapeutic approaches in mice, we generated a mouse model by introducing a premature stop codon in the UGT1a1 gene, which results in an inactive enzyme. Homozygous mutant mice developed severe jaundice soon after birth and died within 11 d, showing significant cerebellar alterations. To rescue neonatal lethality, newborns were injected with a single dose of adeno-associated viral vector 9 (AAV9) expressing the human UGT1A1. Gene therapy treatment completely rescued all AAV-treated mutant mice, accompanied by lower plasma bilirubin levels and normal brain histology and motor coordination. Our mouse model of CNI reproduces genetic and phenotypic features of the human disease. We have shown, for the first time, the full recovery of the lethal effects of neonatal hyperbilirubinemia. We believe that, besides gene-addition-based therapies, our mice could represent a very useful model to develop and test novel technologies based on gene correction by homologous recombination.—Bortolussi, G., Zentilin, L., Baj, G., Giraudi, P., Bellarosa, C., Giacca, M., Tiribelli, C., Muro, A. F. Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer. Federation of American Societies for Experimental Biology 2012-03 /pmc/articles/PMC3370676/ /pubmed/22094718 http://dx.doi.org/10.1096/fj.11-195461 Text en © FASEB This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Communications
Bortolussi, Giulia
Zentilin, Lorena
Baj, Gabriele
Giraudi, Pablo
Bellarosa, Cristina
Giacca, Mauro
Tiribelli, Claudio
Muro, Andrés F.
Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title_full Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title_fullStr Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title_full_unstemmed Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title_short Rescue of bilirubin-induced neonatal lethality in a mouse model of Crigler-Najjar syndrome type I by AAV9-mediated gene transfer
title_sort rescue of bilirubin-induced neonatal lethality in a mouse model of crigler-najjar syndrome type i by aav9-mediated gene transfer
topic Research Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370676/
https://www.ncbi.nlm.nih.gov/pubmed/22094718
http://dx.doi.org/10.1096/fj.11-195461
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