Helper‐dependent adenoviral gene therapy mediates long‐term correction of the clotting defect in the canine hemophilia A model

Background: Adenoviral vector‐mediated gene therapy might have potential for long‐term correction of the monogenic disease hemophilia A. Objective: In this study, we tested the efficacy of administering a helper‐dependent adenoviral vector (HDV) designed for maximal liver‐restricted canine factor VI...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis 2006-06, Vol.4 (6), p.1218-1225
Main Authors: McCORMACK, W. M., SEILER, M. P., BERTIN, T. K., UBHAYAKAR, K., PALMER, D. J., NG, P., NICHOLS, T. C., LEE, B.
Format: Article
Language:English
Subjects:
Adenoviridae - genetics
Animals
Blood Coagulation
Disease Models, Animal
Dogs
Factor VIII - genetics
Factor VIII - metabolism
Factor VIII - therapeutic use
FVII
gene therapy
Genetic Therapy - methods
Genetic Vectors - toxicity
helper‐dependent adenovirus
hemophilia A
Hemophilia A - blood
Hemophilia A - genetics
Hemophilia A - therapy
Liver - metabolism
Mutation
Partial Thromboplastin Time
Whole Blood Coagulation Time
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Summary:Background: Adenoviral vector‐mediated gene therapy might have potential for long‐term correction of the monogenic disease hemophilia A. Objective: In this study, we tested the efficacy of administering a helper‐dependent adenoviral vector (HDV) designed for maximal liver‐restricted canine factor VIII (cFVIII) expression on three out‐bred hemophilia A dogs. Methods: Three FVIII‐deficient animals from the University of North Carolina colony were injected with 1 × 1012 (Dog A), and 3 × 1012 (Dog B and C) vp kg−1 helper‐dependent adenoviral vector, and we performed systematic analysis of toxicity, persistence of therapeutic gene expression, and molecular analysis of gene transfer. Results: We observed acute dose‐dependent elevation in liver enzymes and thrombocytopenia after injection, although both were transient and resolved within 2 weeks. The whole blood clotting time (WBCT), plasma FVIII concentration, FVIII activity, and activated partial thromboplastin time in all animals improved significantly after treatment, and two animals receiving a higher dose reached near normal WBCT with low‐level FVIII activity until terminal sacrifice at 3 months, and 2 years. Importantly, the treated dogs suffered no bleeding events after injection. Moreover, we observed persistent vector‐specific DNA and RNA in liver tissue collected from one high‐dose animal at days 18 and 79, and could not detect the formation of inhibitory antibodies. Conclusion: Although vector‐associated toxicity remains an obstacle, a single injection of HDV led to long‐term transgene expression and vector persistence in two FVIII‐deficient animals with conversion of their severe phenotype to a moderate one.
ISSN:1538-7933
1538-7836
1538-7836
DOI:10.1111/j.1538-7836.2006.01901.x