Preclinical Gene Therapy Studies for Hemophilia Using Adenoviral Vectors

Lieven Thorrez; Thierry VandenDriessche; Désiré Collen; Marinee K. L. Chuah

doi:10.1055/s-2004-825631

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2004; 30(2): 173-183
DOI: 10.1055/s-2004-825631

Preclinical Gene Therapy Studies for Hemophilia Using Adenoviral Vectors

Lieven Thorrez¹ , Thierry VandenDriessche¹ , Désiré Collen¹ , Marinee K. L. Chuah¹ ^, ²

¹Center for Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversity Institute for Biotechnology (VIB), University Hospital Gasthuisberg, Leuven, Belgium
²Professor, Center for Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversity Institute for Biotechnology (VIB), University Hospital Gasthuisberg, Leuven, Belgium

Abstract

Hemophilia A and B are hereditary coagulation defects resulting from a deficiency of factor VIII (FVIII) and factor IX (FIX), respectively. Introducing a functional FVIII or FIX gene could potentially provide a cure for these bleeding disorders. Adenoviral vectors have been used as tools to introduce potentially therapeutic genes into mammalian cells and are by far the most efficient vectors for hepatic gene delivery. Long-term expression of both FVIII and FIX has been achieved in preclinical (hemophilic) mouse models using adenoviral vectors. Therapeutic levels of FVIII and FIX also have been achieved in hemophilic dogs using adenoviral vectors and in some cases expression was long-term. The performance of earlier generation adenoviral vectors, which retained residual viral genes, was compromised by potent acute and chronic inflammatory responses that contributed to significant toxicity and morbidity and short-term expression of FVIII and FIX. The development of improved adenoviral vectors devoid of viral genes (gutless or high-capacity adenoviral vectors) was therefore warranted, which led to a significant reduction in acute and chronic toxicity and more prolonged expression of FVIII and FIX. Strategies aimed at making these vectors safer and less immunogenic and their implications for hemophilia gene therapy are discussed in this review.

KEYWORDS

Hemophilia A - hemophilia B - gene therapy - adenoviral vector

Full Text

References

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Marinee K L ChuahPh.D.

Center for Transgene Technology and Gene Therapy, University of Leuven, Flanders Interuniversity Institute for Biotechnology (VIB), University Hospital Gasthuisberg

Herestraat 49, B-3000 Leuven, Belgium

Email: marinee.chuah@med.kuleuven.ac.be