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 language | English (US) |
|---|---|
| Pages (from-to) | 957-966 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 119 |
| Issue number | 4 |
| DOIs | |
| State | Published - Jan 26 2012 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage. / Binny, Christopher; McIntosh, Jenny; Della Peruta, Marco; Kymalainen, Hanna; Tuddenham, Edward G D; Buckley, Suzanne M K; Waddington, Simon N.; McVey, John H.; Spence, Yunyu; Morton, Christopher L.; Thrasher, Adrian J.; Gray, John T.; Castellino, Francis J.; Tarantal, Alice F; Davidoff, Andrew M.; Nathwani, Amit C.
In: Blood, Vol. 119, No. 4, 26.01.2012, p. 957-966.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage
AU - Binny, Christopher
AU - McIntosh, Jenny
AU - Della Peruta, Marco
AU - Kymalainen, Hanna
AU - Tuddenham, Edward G D
AU - Buckley, Suzanne M K
AU - Waddington, Simon N.
AU - McVey, John H.
AU - Spence, Yunyu
AU - Morton, Christopher L.
AU - Thrasher, Adrian J.
AU - Gray, John T.
AU - Castellino, Francis J.
AU - Tarantal, Alice F
AU - Davidoff, Andrew M.
AU - Nathwani, Amit C.
PY - 2012/1/26
Y1 - 2012/1/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84856296022&partnerID=8YFLogxK
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U2 - 10.1182/blood-2011-09-377630
DO - 10.1182/blood-2011-09-377630
M3 - Article
VL - 119
SP - 957
EP - 966
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -