The immune response in our blood normally serves an important function--preventing foreign
agents, such as bacteria, fungi and viruses, from causing us harm. However, our immune
response can also become a detriment. In the case of hemophilia A – where factor VIII (FVIII) is
infused into the blood – the immune system can produce inhibitory antibodies and prevent clot
formation. Scientists have now developed a method of gene therapy to induce the body to
produce mutant forms of FVIII – such as those with the molecule’s B-domains deleted – altering
the protein’s molecular “fingerprint” while retaining its physiological function. In theory, this
mutant FVIII should evade or “trick” the immune response and allow for normal hemostasis, or
blood clotting, to occur.
A recent study reported the development of a new approach to gene therapy that shields FVIII
produced by the host’s body from the immune response. The study, “Factor VIII Ectopically
Targeted to Platelets is Therapeutic in Hemophilia A with High-Titer Inhibitory Antibodies,”
was published in the July 2006 issue of the Journal of Clinical Investigation.
The strategy of this new gene therapy is to induce platelets, cells that are not only integral to
healthy blood-clot formation but are present wherever a clot needs to be formed, to produce,
store, and release FVIII wherever it is needed. Simultaneously, these platelets were also induced
to express the genes for von Willebrand factor. This protein is not only important to hemostasis,
but is able to preserve the integrity of FVIII even in the caustic environment created by the
Scientists implemented this new approach in mice with hemophilia A. The gene therapy not
only successfully corrected their symptoms of hemophilia A, but was capable of doing so despite
the presence of inhibitors against FVIII. Although scientists have only observed success with this
gene therapy method in mice, they are quickly developing methods and technologies that may
soon be applicable to humans.
Robert R. Montgomery, MD, is a co-author of the study and a member of the National
Hemophilia Foundation’s Medical and Scientific Advisory Council.
Source: Shi Q, Wilcox D, Fahs S, et al. Factor VIII ectopically targeted to platelets is therapeutic
in hemophilia A with high-titer inhibitory antibodies. Journal of Clinical Investigation, July
2006; 116: 1974-1982.