IMR Press / FBS / Volume 4 / Issue 1 / DOI: 10.2741/s269

Frontiers in Bioscience-Scholar (FBS) is published by IMR Press from Volume 13 Issue 1 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Review

Gene-based continuous expression of FVIIa for the treatment of hemophilia

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1 Division of Hematology, The Children’s Hospital of Philadelphia 3501 Civic Center Blvd., 5000 Colket Translational Research Building, Philadelphia, PA 19104
2 Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, 3501 Civic Center Blvd., 5000 Colket Translational Research Building, Philadelphia, PA 19104

*Author to whom correspondence should be addressed.

Academic Editor: L. Vijaya Mohan Rao

Front. Biosci. (Schol Ed) 2012, 4(1), 287–299;
Published: 1 January 2012

Qualitative or quantitative defects in the genes for coagulation factors VIII (FVIII) or IX (FIX) result in a life-threatening, bleeding phenotype (hemophilia A [HA] or B [HB], respectively). Although hemophilia treatment by clotting factor replacement is effective, a proportion of patients develop neutralizing antibodies (inhibitors) to the infused factor that complicate the disease management. For inhibitor patients, recombinant human activated coagulation Factor VII (rhFVIIa), when administered at therapeutic doses, has been shown to bypass the deficiency in FVIII or FIX and result in hemostasis. As an alternative to this protein infusion therapy, a gene-based approach for the treatment of hemophilia with inhibitors has been developed, using continuous expression of a transgene coding for FVIIa following viral-mediated delivery. This approach was validated in hemophilic mice and, notably, in dogs as a model that closely resembles the human disease. In particular, liver-directed FVIIa gene delivery in hemophilic dogs resulted in multi-year transgene expression that ameliorated the bleeding phenotype, without thrombotic complications. These data support the gene-based FVIIa expression as a novel bypass therapy for hemophilia with inhibitors.

Gene Transfer
Large Animal Model
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