AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage

Christopher Binny, Jenny McIntosh, Marco Della Peruta, Hanna Kymalainen, Edward G D Tuddenham, Suzanne M K Buckley, Simon N. Waddington, John H. McVey, Yunyu Spence, Christopher L. Morton, Adrian J. Thrasher, John T. Gray, Francis J. Castellino, Alice F Tarantal, Andrew M. Davidoff, Amit C. Nathwani

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

We explored adeno-associated viral vector (AAV)-mediated gene transfer in the perinatal period in animal models of severe congenital factor VII (FVII) deficiency, a disease associated with early postnatal life-threatening hemorrhage. In young adult mice with plasma FVII < 1% of normal, a single tail vein administration of AAV (1 × 10 13 vector genomes [vg]/kg) resulted in expression of murine FVII at 266% ± 34% of normal for ≥ 67 days, which mediated protection against fatal hemorrhage and significantly improved survival. Codon optimization of human FVII (hFVIIcoop) improved AAV transgene expression by 37-fold compared with the wild-type hFVII cDNA. In adult macaques, a single peripheral vein injection of 2 × 10 11 vg/kg of the hFVIIcoop AAV vector resulted in therapeutic levels of hFVII expression that were equivalent in males (10.7% ± 3.1%) and females (12.3% ± 0.8%). In utero delivery of this vector in the third trimester to fetal monkeys conferred expression of hFVII at birth of 20.4% ± 3.7%, with a gradual decline to > 1% by 7 weeks. Readministration of an alternative serotype at 12 months postnatal age increased hFVII levels to 165% ± 6.2% of normal, which remained at therapeutic levels for a further 28 weeks without toxicity. Thus, perinatal AAV-mediated gene transfer shows promise for disorders with onset of pathology early after birth.

Original languageEnglish (US)
Pages (from-to)957-966
Number of pages10
JournalBlood
Volume119
Issue number4
DOIs
StatePublished - Jan 26 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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