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Title: Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment

item WANG, QIZHAO - Temple University
item Firrman, Jenni
item MOORE, ANDRE - Temple University
item Liu, Linshu
item KOST, JOSEPH - Ben Gurion University Of Negev
item XIAO, WEIDONG - Temple University

Submitted to: Gene Therapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/11/2016
Publication Date: 7/1/2016
Citation: Wang, Q., Firrman, J., Moore, A., Liu, L.S., Kost, J., Xiao, W. 2016. Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment. Gene Therapy. 23(7):597-605. doi: 10.1038/gt.2016.34.

Interpretive Summary: Hemophilia A (HA) is a common blood disease caused by a defect in blood coagulation factor VIII (FVIII). The current therapeutic treatment for the disease is to replace the mutant FVIII with a healthy one; however, it is costly, requires frequent hospital visits, and a person may develop antibodies that can reduce or even eliminate the efficiency of the healthy FVIII. Gene therapy offers an alternative to this classic treatment. However, human FVIII has low efficiency making this strategy impractical. In the present research, we demonstrate that canine FVIII has superior biological properties compared to human FVIII. Based on these results, the engineering of human FVIII to have enhanced efficiency for use in human gene therapy is possible. The current research highlighted a potential to treat human HA using gene therapy.

Technical Abstract: The canine is the most important large animal model for testing novel hemophilia A(HA) treatment. It is often necessary to use canine factor VIII (cFIII) gene or protein for the evaluation of HA treatment in the canine model. However, the different biological properties between cFVIII and human FVIII(hFVIII) indicated that the development of novel HA treatment may require careful characterization of non-human FVIII. To investigate whether the data obtained using cFVIII can translate to HA treatment in human, we analyzed the differential biological properties of canine heavy chain (cHC) and light chain (cLC) by comparing with human HC (hHC) and LC (hLC). The secretion of cHC was 5 approximately 30 fold higher than hHC, with or without LCs. cHC+hLC group exhibited approximately 18-fold increase in coagulation activity compared with hHC+hLC delivery by recombinant adeno-associated viral vectors. Unlike hHC, the secretion of cHC was independent of LCs. cLC improves the specific activity of FVIII by 2 approximately 3-fold compared with hLC. Moreover, the cLC but not cHC, contributes the high stability of cFVIII. Our results suggested that the cFVIII expression results in the canine model should be interpreted with caution as the cHC secreted more efficiently than hHC and cLC exhibited a more active and stable phenotype than hLC.