Liver-directed lentiviral gene therapy in a dog model of hemophilia B.
We investigated the efficacy of liver-directed gene therapy using lentiviral vectors in a large animal model of hemophilia B and evaluated the risk of insertional mutagenesis in tumor-prone mouse models. We showed that gene therapy using lentiviral vectors targeting the expression of a canine factor IX transgene in hepatocytes was well tolerated and provided a stable long-term production of coagulation factor IX in dogs with hemophilia B. By exploiting three different mouse models designed to amplify the consequences of insertional mutagenesis, we showed that no genotoxicity was detected with these lentiviral vectors. Our findings suggest that lentiviral vectors may be an attractive candidate for gene therapy targeted to the liver and may be potentially useful for the treatment of hemophilia.
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy.
Alessio
A
Cantore
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy.
Marco
M
Ranzani
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
Cynthia C
CC
Bartholomae
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy.
Monica
M
Volpin
Coagulation Service and Thrombosis Research Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
Patrizia Della
PD
Valle
Pathology Unit, Department of Oncology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Francesca
F
Sanvito
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
Lucia Sergi
LS
Sergi
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
Pierangela
P
Gallina
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
Fabrizio
F
Benedicenti
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Dwight
D
Bellinger
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Robin
R
Raymer
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Elizabeth
E
Merricks
MolMed S.p.A., 20132 Milan, Italy.
Francesca
F
Bellintani
Généthon, 91000 Évry, France.
Samia
S
Martin
Pathology Unit, Department of Oncology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Claudio
C
Doglioni
Coagulation Service and Thrombosis Research Unit, San Raffaele Scientific Institute, 20132 Milan, Italy.
Armando
A
D'Angelo
Department of Gene Therapy and Regenerative Medicine, Free University of Brussels, 1050 Brussels, Belgium. Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Thierry
T
VandenDriessche
Department of Gene Therapy and Regenerative Medicine, Free University of Brussels, 1050 Brussels, Belgium. Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, 3000 Leuven, Belgium.
Marinee K
MK
Chuah
Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany.
Manfred
M
Schmidt
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Timothy
T
Nichols
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy.
Eugenio
E
Montini
San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. Vita-Salute San Raffaele University, 20132 Milan, Italy. naldini.luigi@hsr.it.
Luigi
L
Naldini
D000818:Animals; D001777:Blood Coagulation; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000378:metabolism; D002836:Hemophilia B / Q000628:therapy*; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009153:Mutagens / Q000633:toxicity; D013997:Time Factors; D014161:Transduction, Genetic; D019076:Transgenes
D009153:Mutagens