Successful Transduction of Liver in Hemophilia By AAV-Factor IX and Limitations Imposed by The Host Immune Response
| dc.contributor.author | Manno, Catherine S. | |
| dc.contributor.author | Arruda, Valder R. | |
| dc.contributor.author | Kaye, Robin | |
| dc.contributor.author | Nakai, Hiroyuki | |
| dc.contributor.author | Sabatino, Denise | |
| dc.date.accessioned | 2024-12-15T20:10:35Z | |
| dc.date.available | 2024-12-15T20:10:35Z | |
| dc.date.issued | 2006-02-12 | |
| dc.description.abstract | We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B1. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 × 1012 vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of ∼8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression. | |
| dc.identifier.citation | Manno, C. S., Pierce, G. F., Arruda, V. R., Glader, B., Ragni, M., Rasko, J. J., ... & Kay, M. A. (2006). Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nature medicine, 12(3), 342-347.https://doi.org/10.1038/nm1358 | |
| dc.identifier.issn | 1546-170X | |
| dc.identifier.uri | https://nru.uncst.go.ug/handle/123456789/9725 | |
| dc.language.iso | en | |
| dc.publisher | Nature medicine | |
| dc.title | Successful Transduction of Liver in Hemophilia By AAV-Factor IX and Limitations Imposed by The Host Immune Response |