Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice

T. P. Zhang, D. Y. Jin, R. M. Wardrop, T. Gui, R. Maile, J. A. Frelinger, D. W. Stafford, P. E. Monahan

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Immune responses leading to antibody-mediated elimination of the transgenic protein are a concern in gene replacement for congenital protein deficiencies, for which hemophilia is an important model. Although most hemophilia B patients have circulating non-functional but immunologically crossreactive factor IX (FIX) protein (CRM+ phenotype), inciting factors for FIX neutralizing antibody (inhibitor) development have been studied in crossreactive material-negative (CRM-) animal models. For this study, determinants of FIX inhibitor development were compared in hemophilia B mice, in which circulating FIX protein is absent (CRM- factor IX knockout (FIXKO) model) or present (CRM+ missense R333Q-hFIX model) modeling multiple potential therapies. The investigations compare for the first time different serotypes of adeno-associated virus (AAV) vectors (AAV2 and AAV1), each at multiple doses, in the setting of two different FIX mutations. The comparisons demonstrate in the FIXKO background (CRM- phenotype) that neither vector serotype nor vector particle number independently determine the inhibitor trigger, which is influenced primarily by the level and kinetics of transgene expression. In the CRM+ missense background, inhibitor development was never stimulated by AAV gene therapy or protein therapy, despite the persistence of lymphocytes capable of responding to FIX with non-inhibitory antibodies. This genotype/ phenotype is strongly protective against antibody formation in response to FIX therapy.

Original languageEnglish (US)
Pages (from-to)429-440
Number of pages12
JournalGene Therapy
Volume14
Issue number5
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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