A step toward liver gene therapy: efficient correction of the genetic defect of hepatocytes isolated from a patient with Crigler-Najjar syndrome type 1 with lentiviral vectors.

Détails

ID Serval
serval:BIB_3FA49A9976E9
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
A step toward liver gene therapy: efficient correction of the genetic defect of hepatocytes isolated from a patient with Crigler-Najjar syndrome type 1 with lentiviral vectors.
Périodique
Transplantation
Auteur(s)
Birraux J., Menzel O., Wildhaber B., Jond C., Nguyen T.H., Chardot C.
ISSN
1534-6080 (Electronic)
ISSN-L
0041-1337
Statut éditorial
Publié
Date de publication
2009
Peer-reviewed
Oui
Volume
87
Numéro
7
Pages
1006-1012
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
BACKGROUND: Ex vivo liver gene therapy may be a future alternative to orthotopic liver transplantation for the treatment of some liver diseases. We previously described the transduction in suspension with lentiviral vectors and immediate hepatocyte transplantation (SLIT) protocol and its high transduction rate with normal human hepatocytes. We also reported SLIT efficiency in the animal model of Crigler-Najjar type 1 syndrome (CN-1), the Gunn rat. Here, we evaluated SLIT efficiency with diseased human hepatocytes.
METHODS: Hepatocytes of the liver from a 4-year-old patient presenting CN-1 were isolated. They were transduced with liver-specific lentiviral vectors expressing uridine-diphosphate-glucuronosyltransferase (hUGT1A1) or green fluorescent protein, and then analyzed in vitro for transduction efficiency and hUGT1A1 expression, or transplanted in nonobese diabetic/severe combined immunodeficiency (SCID) mice to evaluate long-term survival of transplanted cells.
RESULTS: More than 90% of CN-1 hepatocytes were transduced. Hepatocytes produced hUGT1A1 protein after lentiviral transduction. After having been subjected to the SLIT, lentivirally transduced CN-1 hepatocytes engrafted long term (up to 26 weeks posttransplantation) in recipient livers and expressed green fluorescent protein or hUGT1A1 vector.
CONCLUSION: The SLIT protocol allowed for a high transduction of CN-1 hepatocytes and restoration of the expression of the deficient protein. Furthermore, long-term survival of lentivirally transduced CN-1 hepatocytes in the liver of immunodeficient mice was demonstrated. This study is therefore an important step toward human application of lentiviral gene therapy.
Mots-clé
Animals, Child, Preschool, Crigler-Najjar Syndrome/genetics, Cryopreservation/methods, Female, Genetic Therapy, Genetic Vectors, Glucuronosyltransferase/genetics, Hepatectomy, Hepatocytes/cytology, Hepatocytes/physiology, Humans, Lentivirus/genetics, Mice, Mice, Inbred NOD, Mice, SCID
Pubmed
Web of science
Création de la notice
21/02/2015 10:17
Dernière modification de la notice
03/03/2018 16:25
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