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 journalArticle

31 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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    Binny, C., McIntosh, J., Della Peruta, M., Kymalainen, H., Tuddenham, E. G. D., Buckley, S. M. K., Waddington, S. N., McVey, J. H., Spence, Y., Morton, C. L., Thrasher, A. J., Gray, J. T., Castellino, F. J., Tarantal, A. F., Davidoff, A. M., & Nathwani, A. C. (2012). AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage. Blood, 119(4), 957-966. https://doi.org/10.1182/blood-2011-09-377630