{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T01:09:28Z","timestamp":1773277768558,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2004,10,18]],"date-time":"2004-10-18T00:00:00Z","timestamp":1098057600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Gene Medicine"],"published-print":{"date-parts":[[2004,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>The development of anti\u2010factor VIII (FVIII) antibodies (inhibitors) is a critical concern when considering gene therapy as a potential treatment modality for hemophilia A. We used a hemophilia A mouse model bred on different genetic backgrounds to explore genetically controlled differences in the immune response to FVIII gene therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>C57BL\/6 FVIII knockout (C57\u2010FVIIIKO) mice were bred with normal BALB\/c (BAL) mice, to generate a recombinant congenic BAL\u2010FVIIIKO model of hemophilia A. Early generation adenoviral (Ad) vectors containing the canine FVIII B\u2010domain\u2010deleted transgene under the control of either the CMV promoter or a tissue\u2010restricted (TR) promoter were administered to C57\u2010FVIIIKO, C57xBAL(F1)\u2010FVIIIKO crosses, and BAL\u2010FVIIIKO mice. FVIII expression, inhibitor development, inflammation, and vector\u2010mediated toxicity were assessed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In response to administration of Ad\u2010CMV\u2010cFVIII, C57\u2010FVIIIKO mice attain 3\u2010fold higher levels of FVIII expression than BAL\u2010FVIIIKO. All strains injected with Ad\u2010CMV\u2010FVIII displayed FVIII expression lasting only 2 weeks, with associated inhibitor development. C57\u2010FVIII\u2010KO mice that received Ad\u2010TR\u2010FVIII expressed FVIII for 12 months post\u2010injection, whereas FVIII expression was limited to 1 week in C57xBAL(F1)\u2010FVIIIKO and BAL\u2010FVIIIKO mice. This loss of expression was associated with anti\u2010FVIII inhibitor development. BAL\u2010FVIIIKO mice showed increased hepatotoxicity with alanine aminotransferase levels reaching 4\u2010fold higher levels than C57\u2010FVIIIKO mice. However, C57\u2010FVIIIKO mice initiate a more rapid and effective cell\u2010mediated clearance of virally transduced cells than BAL\u2010FVIIIKO, as evidenced by real\u2010time PCR analysis of transduced tissues. Overall, strain\u2010dependent differences in the immune response to FVIII gene delivery were only noted in the adaptive response, and not in the innate response.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results indicate that the genetic background of the murine model of hemophilia A influences FVIII expression levels, the development of anti\u2010FVIII inhibitors, clearance of transduced cells, and the severity of vector\u2010mediated hepatotoxicity. Copyright \u00a9 2004 John Wiley &amp; Sons, Ltd.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jgm.624","type":"journal-article","created":{"date-parts":[[2004,10,18]],"date-time":"2004-10-18T18:08:20Z","timestamp":1098122900000},"page":"1358-1368","source":"Crossref","is-referenced-by-count":25,"title":["Heterogeneity of the immune response to adenovirus\u2010mediated factor VIII gene therapy in different inbred hemophilic mouse strains"],"prefix":"10.1002","volume":"6","author":[{"given":"Fiona E. 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