Gene Therapy for Hemophilia B: Host Immunosuppression Prolongs the Therapeutic Effect of Adenovirus-Mediated Factor IX Expression

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Abstract
Hemophilia B is caused by a deficiency of blood clotting factor IX (FIX). Previous studies have shown that the delivery of a recombinant adenoviral vector expressing canine FIX (cFIX) resulted in a complete correction of hemophilia B in FIX-deficient dogs, but that cFIX expression decreased to only about 1–2% of normal levels 3 weeks after treatment. In the present study, therapeutic levels of cFIX expression capable of producing a partial correction of hemophilia B were maintained for at least 6 months after the coadministration of the cFIX-expressing adenovirus and the immunosuppressive agent cyclosporin A (CsA). These findings support a recent report (Yang et al., 1994) that host T-cell-mediated immunity against virally transduced cells is a major contributing factor to the transient nature of adenovirus-mediated gene expression in immunocompetent animals. Although a second administration of the cFIX-expressing adenovirus 6 months after the first infusion had only a minimal effect on plasma FIX levels in a dog that had been continuously treated with CsA, the prolonged expression of the transgene indicates that immunosuppression may be applicable in attaining long-term treatment of clinically relevant disorders. Adenovirus-mediated gene transfer in vivo results in efficient but transient transgene expression. Recent studies have suggested that this loss of expression is caused by the destruction of adenovirally transduced cells by the host immune system. If true, suppression of the immune system should significantly prolong the effects of adenoviral treatment This hypothesis was examined by combining adenovirus-mediated transfer of the canine factor IX cDNA with continuous immunosuppression in a dog model for hemophilia B. Immunosuppression significantly increased the persistence of transgene expression following adenovirus-mediated transfer in vivo. This result suggests that further modifications of adenoviral vectors that reduce their immunogenicity may significantly increase their persistence in vivo.