AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage
| Autor: | Christopher Binny, Christopher L. Morton, Adrian J. Thrasher, John T. Gray, John H. McVey, Alice F. Tarantal, Amit C. Nathwani, Andrew M. Davidoff, Hanna Kymalainen, Francis J. Castellino, Edward G. D. Tuddenham, Suzanne M. K. Buckley, Yunyu Spence, Simon N. Waddington, Jenny McIntosh, Marco Della Peruta |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Factor VII Deficiency Gene Expression Physiology 030204 cardiovascular system & hematology Biochemistry Thrombosis and Hemostasis Mice chemistry.chemical_compound 0302 clinical medicine Pregnancy Young adult Fetal Therapies Sex Characteristics 0303 health sciences Factor VII Hep G2 Cells Gene Therapy Hematology Dependovirus 3. Good health Perinatal Care Injections Intravenous Toxicity Female Genetic Vectors Immunology Hemorrhage Viral vector 03 medical and health sciences medicine Animals Humans Codon Survival analysis 030304 developmental biology Fetus business.industry Genetic Therapy Cell Biology medicine.disease Macaca mulatta Survival Analysis Postnatal age Animals Newborn chemistry business |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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 × 1013 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 × 1011 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. |
| Databáze: | OpenAIRE |
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