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Publication Detail
Therapeutic levels of FVIII following a single peripheral vein administration of rAAV vector encoding a novel human factor VIII variant.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    McIntosh J, Lenting PJ, Rosales C, Lee D, Rabbanian S, Raj D, Patel N, Tuddenham EGD, Christophe OD, McVey JH, Waddington S, Nienhuis AW, Gray JT, Fagone P, Mingozzi F, Zhou S-Z, High KA, Cancio M, Ng CYC, Zhou J, Morton CL, Davidoff AM, Nathwani AC
  • Publication date:
  • Pagination:
    3335, 3344
  • Journal:
  • Volume:
  • Issue:
  • Status:
  • Country:
    United States
  • PII:
  • Language:
  • Keywords:
    Animals, Blotting, Western, Dependovirus, Factor VIII, Genetic Therapy, Genetic Variation, Genetic Vectors, Glycosylation, Hemophilia A, Humans, Immune Tolerance, Liver, Macaca mulatta, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Peptide Fragments, Promoter Regions, Genetic
Recombinant adeno-associated virus (rAAV) vectors encoding human factor VIII (hFVIII) were systematically evaluated for hemophilia A (HA) gene therapy. A 5.7-kb rAAV-expression cassette (rAAV-HLP-codop-hFVIII-N6) containing a codon-optimized hFVIII cDNA in which a 226 amino acid (aa) B-domain spacer replaced the entire B domain and a hybrid liver-specific promoter (HLP) mediated 10-fold higher hFVIII levels in mice compared with non-codon-optimized variants. A further twofold improvement in potency was achieved by replacing the 226-aa N6 spacer with a novel 17-aa peptide (V3) in which 6 glycosylation triplets from the B domain were juxtaposed. The resulting 5.2-kb rAAV-HLP-codop-hFVIII-V3 cassette was more efficiently packaged within AAV virions and mediated supraphysiologic hFVIII expression (732 ± 162% of normal) in HA knock-out mice following administration of 2 × 10(12) vector genomes/kg, a vector dose shown to be safe in subjects with hemophilia B. Stable hFVIII expression at 15 ± 4% of normal was observed at this dose in a nonhuman primate. hFVIII expression above 100% was observed in 3 macaques that received a higher dose of either this vector or the N6 variant. These animals developed neutralizing anti-FVIII antibodies that were abrogated with transient immunosuppression. Therefore, rAAV-HLP-codop-hFVIII-V3 substantially improves the prospects of effective HA gene therapy.
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