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

Binny, C, McIntosh, J, Della Peruta, M, Kymalainen, H, Tuddenham, EG, Buckley, SM, Waddington, SN, McVey, JH, Spence, Y, Morton, CL , Thrasher, AJ, Gray, JT, Castellino, FJ, Tarantal, AF, Davidoff, AM and Nathwani, AC (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). pp. 957-966.

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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. Re-administration 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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Binny, C
McIntosh, J
Della Peruta, M
Kymalainen, H
Tuddenham, EG
Buckley, SM
Waddington, SN
Spence, Y
Morton, CL
Thrasher, AJ
Gray, JT
Castellino, FJ
Tarantal, AF
Davidoff, AM
Nathwani, AC
Date : 26 January 2012
DOI : 10.1182/blood-2011-09-377630
Uncontrolled Keywords : Animals, Animals, Newborn, Codon, Dependovirus, Factor VII, Factor VII Deficiency, Female, Fetal Therapies, Gene Expression, Genetic Therapy, Genetic Vectors, Hemorrhage, Hep G2 Cells, Humans, Injections, Intravenous, Macaca mulatta, Male, Mice, Perinatal Care, Pregnancy, Sex Characteristics, Survival Analysis
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 09:56
Last Modified : 24 Jan 2020 18:05

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