[Frontiers in Bioscience S4, 287-299, January 1, 2012]

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

Paris Margaritis1,2

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

TABLE OF CONTENTS

1. Abstract
2. Introduction
3.1. Coagulation overview
3.2. The bleeding phenotype in hemophilia and its current treatment
3.3. Development of neutralizing antibodies in hemophilia patients
3.4. The concept of gene therapy for hemophilia
3.5. Immunologic considerations for hemophilia gene therapy with FVIII or FIX
3.6. Gene-based bypass therapy for hemophilia
3.7. Development of a FVIIa transgene
3.8. The safety profile of FVIIa gene transfer - lessons from a mouse hemophilia model
3.9. Overexpression of FVIIa in a large animal model of hemophilia
3.9.1. Efficacy data
3.9.2. Safety data
4. Perspective
5. Acknowledgments
6. References

1. ABSTRACT

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.