Similar to any novel treatment strategy for hemophilia, gene therapy faces the question
of the risk of formation of inhibitory antibodies to the therapeutic factor VIII or
factor IX protein. Activation of CD4+ or CD8+ T cells could lead to antibody formation or cytotoxic T lymphocyte responses to transgene-expressing
cells. Preclinical studies in animal models of hemophilia A and B with different mutations
in the dysfunctional gene shed light on the risk for such immune responses and point
toward strategies to avoid immune activation or even promote tolerance induction.
The impacts of variables such as choice and design of gene transfer vector, underlying
gene mutation, route of vector administration, and transient immune suppression are
discussed. Maintenance of immunological hyporesponsiveness to the therapeutic gene
product is critical for successful gene therapy. Recent studies provide evidence for
tolerance induction to coagulation factor antigens by viral hepatic or neonatal in
vivo gene transfer, by in utero gene delivery, and by oral or nasal administration
of protein or peptides.
KEYWORDS
Immune response - inhibitor - T cell - B cell - cytotoxic T lymphocyte
REFERENCES
in vivo.
.
Hum Gene Ther.
1999;
10
965-976
rwherzog@mail.med.upenn.edu
