126R.W. Herzogopment of the immune system in the setting ofa null mutation. The risk of inhibitor formationcan be substantially reduced by transientimmune modulation or by hepatic gene transfer,which may not elicit an anti-F.IX response evenin animal models that are at risk of inhibitor formationin protein-based therapy.AcknowledgmentsRWH is supported by a Career Development awardfrom the National Hemophilia Foundation (USA).The majority of the work described here is supportedby NIH grants P01 HL64190 and R01 HL61921 toK.A. High. The author is grateful for the support andcontributions of Drs. K.A. High, V.R. Arruda, P.A.Fields, C.D. Lothrop Jr., L.B. Couto, and T.C.Nichols.References1. High KA. Factor IX: molecular structure, epitopes, andmutations associated with inhibitor formation. In: AledortLM, Hoyer LW, Lusher JM, Reisner HM, White GC,eds. Advances in Experimental Medicine and Biology.Vol. 386:79-86, New York, Plenum Press, 1995.2. Hoyer LW. The incidence of factor VIII inhibitors inpatients with severe hemophilia A. Adv Exper Med &Biol 1995;386:35-463. High KA. Gene transfer as an approach to treatinghemophilia. Circ Res 2001;88:137-44.4. High KA. Gene therapy: a 2001 perspective. Haemophilia2001; 7 Suppl 1:23-7.5. Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB,McClelland A, et al. Evidence for gene transfer andexpression of factor IX in haemophilia B patients treatedwith an AAV vector. Nature Genet 2000;24:257-616. Roth DA, O'Brien J, Treco DA, Selden RF. Non-viraltransfer of the gene encoding coagulation factor VIII inpatients with secere hemophilia A. N Engl J Med 2001;344:1738-42.7. Fields PA, Kowalczyk DW, Arruda VR, McCleland ML,Hagstrom JN, KJ P, et al. Choice of vector determines Tcell subsets involved in immune responses against thesecreted transgene product factor IX. Mol Ther 2000;1:225-35.8. Herzog RW, Yang EY, Couto LB, Hagstrom JN, Elwell D,Fields PA, et al. Long-term correction of canine hemophiliaB by gene transfer of blood coagulation factor IXmediated by adeno-associated viral vector. Nat Med1999;5:56-63.9. Snyder RO, Miao C, Meuse L, Tubb J, Donahue BA, LinH-F, et al. Correction of hemophilia B in canine andmurine models using recombinant adeno-associatedviral vectors. Nat Med 1999;5:64-70.10. Wang L, Takabe K, Bidlingmaier SM, Ill CR, Verma IM.Sustained correction of bleeding disorder in hemophiliaB mice by gene therapy. Proc Natl Acad Sci USA 1999;96:3906-1011. Wang L, Nichols TC, Read MS, D.A. B, Verma IM. Sustainedexpression of therapeutic level of factor IX inhemophilia B dogs by AAV-mediated gene therapy inliver. Mol Ther 2000;1:154-812. Chao H, Samulski R, Bellinger D, Monahan P, NicholsT, Walsh C. Persistent expression of canine factor IX inhemophilia B canines. Gene Ther 1999;6:1695-70413. Carter PJ, Samulski RJ. Adeno-associated viral vectorsas gene delivery vehicles. Int J Mol Med 2000; 6:17-2714. 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NEngl J Med 1988;318:947-50.24. Evans JP, Brinkhous KM, Brayer GD, Reisner HW, HighKA. Canine hemophilia B resulting from a point mutationwith unusual consequences. Proc Natl Acad SciUSA 1989;86:10095-9.25. Herzog RW, Arruda VR, Fisher TH, Read MS, NichiolsTC, High KA. Absence of circulating factor IX antigen inhemophilia B dogs of the UNC-Chapel Hill colony.Thromb Haemostas 2000;84:352-4.26. Mount JD, Herzog RW, Tillson DM, Goodman SA,Robinson N, McCleland ML, et al. Sustained phenotypiccorrection of hemophilia B dogs with a factor IXnull mutation by liver-directed gene therapy. Blood2002;99:2670-6.27. Chao H, Liu Y, Rabinowitz J, Li C, Samulski RJ, WalshCE. Several log increase in therapeutic transgene deliveryby distinct adeno-associated viral serotype vectors.Mol Ther 2000;2:619-23.28. Xiao W, Chirmule N, Berta SC, McCullough B, Gao G,Wilson JM. Gene therapy vectors based on adeno-associatedvirus type 1. J Virol 1999;73:3994-4003.29. Herzog RW, Mount JD, Arruda VR, High KA, LothropCDJ. Muscle-directed gene transfer and transientimmune suppression result in sustained partial correctionof canine hemophilia B caused by a null mutation.Mol Ther 2001;4:192-200.30. Mauser AE, Whitlark J, Whitney KM, Lothrop CD Jr. Adeletion mutation causes hemophilia B in Lhasa Apsodogs. Blood 1996;88:3451-5.31. Fields P, Armstrong E, Hagstrom JN, Arruda VR, MurphyML, Farrell JP, High KA, Herzog RW. Intravenousadministration of an E1/E3-deleted adenoviral vectorinduces tolerance to factor IX in C57BL/6 mice. GeneTherapy 2001;8:354-61.32. Michou A, Santoro L, Christ M, Julliard V, Pavirani A,Mehtali M. Adenovirus-mediated gene transfer: influenceof transgene, mouse strain and type of immuneresponse on persistence of transgene expression. GeneTher 1997;4:473-82.33. Nathwani AC, Davidoff A, Hanawa H, Zhou JF, VaninEF, Nienhuis AW. 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Index of authorsAhmad, R.U., 56Albert, T., 78Astermark, J., 30,46,72Baudo, F., 93Berntorp, E., 26,30,46,72Brackmann, H.H., 78Bril, W.S., 18Brito, D., 43Chuah, M.K.L., 115Collen, D., 115de Cataldo, F., 93Effenberger, W., 78Gilles, J.G., 53Goodeve, A., 2Hampel, H., 86Hanfland, P., 78Hausl, Ch., 56Haya, S., 43Herzog, R.W., 122Hess, L., 78Hodes, R.J., 100Huth-Kühne, A., 86Jacquemin, M.G., 65Kaveri, S., 49Kazatchkine, M.D., 49Kobelt, R., 41Lacroix-Desmazes, S., 49Lages, P., 86Lillicrap, D., 75,111Ljung, R.C.R., 4Lollar, P., 11Lopez-Fernandez, MF., 43Maier, E., 56Mauser-Bunschoten, E.P., 35Mostarda, G., 93Nemes, L., 106Nettekoven, W., 78Oldenburg, J., 78Pitlik, E., 106Reipert, B.M., 56Rodriguez-Martorell, F., 43Roosendaal, G., 35Saint-Remy, J.M.R., 8,65,67Sasgary, M., 56Schwaab, R., 78Schwarz, H.P., 56Sosa, R., 43Turecek, P.L., 56Tusell, J., 43Unkrig, Ch., 78Vacchio, M.S., 100van den Berg, H.M., 35van den Brink, E.N., 18VandenDriessche, T., 115Vetter, H., 78Villar, A., 43Voorberg, J., 18Warrier, I., 70Zeitler, H., 78Zimmermann, R., 86
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