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Report on Long-Term Factor VIII Expression from Gene Therapy

An advance in the field of gene therapy for hemophilia has recently been reported in the July 1,
2006 issue of Blood. The article, “Multiyear Therapeutic Benefit of AAV Serotypes 2, 6, and 8
Delivering Factor VIII to Hemophilia A Mice and Dogs,” described the first study showing the
production of Factor VIII (FVIII) at physiologically significant levels for several years using
varying types of adeno-associated virus vectors (AAV). Study authors Dr. Haiyan Jiang and
colleagues have reportedly developed a method that has essentially “cured” the mice and dogs
with hemophilia A within the duration of their study.

Previous AAV studies revealed only short-term success with AAV-induced FVIII production in
mice. Contributing to the difficulties of developing a successful form of gene therapy for
hemophilia A treatment is the fact that FVIII is an immunogenic protein, a substance that readily
induces the body’s immune response, causing it to form inhibitor antibodies that prevent clot
formation. By mutating the gene for FVIII (or specifically deleting the B-domain of canine-
FVIII), Jiang and colleagues were able to induce dogs and mice with hemophilia to produce a
mutant form of FVIII that was not hindered by the immune response. They successfully
overcame a barrier that has traditionally hampered previous gene therapy trials in hemophilia. 

By building on previous knowledge gathered from AAV studies in mice, Jiang and colleagues
applied the techniques to dogs. They also discovered differences in the tropisms – affinity for
vectors for different types of cells – exhibited by different types of AAV between species. This
underscores that what is applicable to mice and dogs may not necessarily translate directly to
humans. Still, by developing a successful method of inducing dogs and mice with hemophilia A
to produce therapeutically significant levels of FVIII for long periods, Jiang and colleagues have
established a strong foundation for future research in the field.

One of the co-authors of the study is David Lillicrap, MD, FRCPC, Professor of Pathology and
Molecular Medicine at Queen's University in Kingston, Ontario, Canada. Dr. Lillicrap is a
member of the National Hemophilia Foundation’s Medical and Scientific Advisory Council.

The study was funded by Bayer HealthCare and the Canadian Institutes of Health Research.

Source: Jiang H, Lillicrap D, Patarroyo-White S, et al. Multiyear therapeutic benefit of AAV
serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood. July 1, 2006;
108: 107-115.


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