Research ArticleGene Therapy

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

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Science Translational Medicine  04 Mar 2015:
Vol. 7, Issue 277, pp. 277ra28
DOI: 10.1126/scitranslmed.aaa1405

Advancing gene therapy for hemophilia

Hemophilia is an inherited bleeding disorder caused by a deficiency in a blood clotting factor. The current treatment requires lifelong intravenous administration of the missing clotting factor every few days, a costly and demanding regimen for patients with hemophilia. Gene therapy has the potential to provide a single-shot treatment option by replacing a functional gene in liver cells that naturally produce the factor. Cantore et al. now report a study of the efficacy and safety of liver-directed in vivo gene therapy in large and small animal models using lentiviral vectors. This gene therapy strategy with lentiviral vectors may complement the use of other gene therapy vectors for treating hemophilia.


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.

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