Gene therapy for hemophilia B: host immunosuppression prolongs the therapeutic effect of adenovirus-mediated factor IX expression.
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.
Fang
B
B
Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Eisensmith
R C
RC
Wang
H
H
Kay
M A
MA
Cross
R E
RE
Landen
C N
CN
Gordon
G
G
Bellinger
D A
DA
Read
M S
MS
Hu
P C
PC
D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001777:Blood Coagulation; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D005164:Factor IX / Q000096:biosynthesis / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D002836:Hemophilia B / Q000097:blood / Q000628:therapy*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009500:Neutralization Tests
D000914:Antibodies, Viral; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D005164:Factor IX