title: AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage.
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. 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.
authors: University College London Cancer Institute, London, UK.
authors: Christopher
authors: C
authors: Binny
authors: Jenny
authors: J
authors: McIntosh
authors: Marco
authors: M
authors: Della Peruta
authors: Hanna
authors: H
authors: Kymalainen
authors: Edward G D
authors: EG
authors: Tuddenham
authors: Suzanne M K
authors: SM
authors: Buckley
authors: Simon N
authors: SN
authors: Waddington
authors: John H
authors: JH
authors: McVey
authors: Yunyu
authors: Y
authors: Spence
authors: Christopher L
authors: CL
authors: Morton
authors: Adrian J
authors: AJ
authors: Thrasher
authors: John T
authors: JT
authors: Gray
authors: Francis J
authors: FJ
authors: Castellino
authors: Alice F
authors: AF
authors: Tarantal
authors: Andrew M
authors: AM
authors: Davidoff
authors: Amit C
authors: AC
authors: Nathwani
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003062:Codon; D000229:Dependovirus / Q000235:genetics; D005167:Factor VII / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D005168:Factor VII Deficiency / Q000097:blood / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D046128:Fetal Therapies / Q000009:adverse effects; D015870:Gene Expression; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D056945:Hep G2 Cells; D006801:Humans; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D018743:Perinatal Care; D011247:Pregnancy; D012727:Sex Characteristics; D016019:Survival Analysis
chemical_list: D003062:Codon; D005167:Factor VII