Liver-directed lentiviral gene therapy in a dog model of hemophilia B

被引：120

作者：

Cantore, Alessio ^{[1
,2
]}

Ranzani, Marco ^{[1
,2
]}

Bartholomae, Cynthia C. ^{[3
,4
]}

Volpin, Monica ^{[1
,2
]}

Della Valle, Patrizia ^{[5
,6
]}

Sanvito, Francesca ^{[7
]}

Sergi, Lucia Sergi ^{[1
]}

Gallina, Pierangela ^{[1
]}

Benedicenti, Fabrizio ^{[1
]}

Bellinger, Dwight ^{[8
]}

Raymer, Robin ^{[8
]}

Merricks, Elizabeth ^{[8
]}

Bellintani, Francesca ^{[9
]}

Martin, Samia ^{[10
]}

Doglioni, Claudio ^{[7
]}

D'Angelo, Armando ^{[5
,6
]}

VandenDriessche, Thierry ^{[11
,12
]}

Chuah, Marinee K. ^{[11
,12
]}

Schmidt, Manfred ^{[3
,4
]}

Nichols, Timothy ^{[8
]}

Montini, Eugenio ^{[1
]}

Naldini, Luigi ^{[1
,2
]}

机构：

[1] Ist Sci San Raffaele, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy

[2] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[3] Natl Ctr Tumor Dis, Dept Translat Oncol, D-69120 Heidelberg, Germany

[4] German Canc Res Ctr, D-69120 Heidelberg, Germany

[5] Ist Sci San Raffaele, Coagulat Serv, I-20132 Milan, Italy

[6] Ist Sci San Raffaele, Thrombosis Res Unit, I-20132 Milan, Italy

[7] Ist Sci San Raffaele, Dept Oncol, Pathol Unit, I-20132 Milan, Italy

[8] Univ N Carolina, Dept Pathol, Chapel Hill, NC 27599 USA

[9] MolMed SpA, I-20132 Milan, Italy

[10] Genethon, F-91000 Evry, France

[11] Free Univ Brussels, Dept Gene Therapy & Regenerat Med, B-1050 Brussels, Belgium

[12] Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, B-3000 Louvain, Belgium

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2015年 / 7卷 / 277期

基金：

欧洲研究理事会;

关键词：

HUMAN-FACTOR-IX; TRANSGENE EXPRESSION; MOUSE MODEL; IN-VIVO; ENDOGENOUS MICRORNA; VECTOR INTEGRATION; LOW GENOTOXICITY; MICE; ONCOGENESIS; MUTATIONS;

D O I：

10.1126/scitranslmed.aaa1405

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：11

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