Linked Life Data

20539913

Source:http://linkedlifedata.com/resource/pubmed/id/20539913

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
2
pubmed:dateCreated
2010-8-4
pubmed:abstractText
Engineered recombinant factor IX (FIX) with augmented clotting activity may prove useful for replacement therapy, but it has not been studied for risk of thrombosis. We used three mouse models to evaluate thrombosis risk associated with the FIX variant FIX-Triple, which has a 13-fold higher specific activity than wild-type FIX (FIX-WT). Protein infusion of FIX-Triple into haemophilia B mice was not thrombogenic, even at a dose of 13-fold higher than FIX-WT. Gene knock-in to generate mice that constitutively produce FIX-WT or FIX-Triple protein revealed that all mice expressed equal antigen levels. FIX-Triple knock-in mice that exhibited 10-fold higher FIX clotting activity did not show hypercoagulation. Adeno-associated viral (AAV) delivery of the FIX gene into mice was used to mimic gene therapy. Haemophilia B and inbred C57Bl/6 mice injected with different doses of virus particles carrying FIX-WT or FIX-Triple and expressing up to a nearly 13-fold excess (1289% of normal) of FIX clotting activity did not show increased risk of thrombosis compared with untreated wild-type mice in a normal haemostatic state. When challenged with ferric chloride (FeCl3), the mesenteric venules of AAV-treated C57Bl/6 mice that gave a nearly five-fold excess (474%) of FIX clotting activity were not thrombotic; however, thrombosis became obvious in FeCl3-challenged mice expressing extremely high FIX clotting activities (976-1289%) achieved by AAV delivery of FIX-Triple. These studies suggest that FIX-Triple is not thrombogenic at therapeutic levels and is a potential therapeutic substitute for FIX-WT.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0340-6245
pubmed:author
pubmed:issnType
Print
pubmed:volume
104
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
355-65
pubmed:dateRevised
2011-5-23
pubmed:meshHeading
pubmed-meshheading:20539913-Animals, pubmed-meshheading:20539913-Chlorides, pubmed-meshheading:20539913-Coagulants, pubmed-meshheading:20539913-Dependovirus, pubmed-meshheading:20539913-Disease Models, Animal, pubmed-meshheading:20539913-Dose-Response Relationship, Drug, pubmed-meshheading:20539913-Factor IX, pubmed-meshheading:20539913-Ferric Compounds, pubmed-meshheading:20539913-Gene Therapy, pubmed-meshheading:20539913-Genetic Vectors, pubmed-meshheading:20539913-Hemophilia B, pubmed-meshheading:20539913-Hemostasis, pubmed-meshheading:20539913-Humans, pubmed-meshheading:20539913-Infusions, Intravenous, pubmed-meshheading:20539913-Laser-Doppler Flowmetry, pubmed-meshheading:20539913-Mice, pubmed-meshheading:20539913-Mice, Inbred C57BL, pubmed-meshheading:20539913-Mice, Mutant Strains, pubmed-meshheading:20539913-Mice, Transgenic, pubmed-meshheading:20539913-Mutation, pubmed-meshheading:20539913-Recombinant Proteins, pubmed-meshheading:20539913-Risk Assessment, pubmed-meshheading:20539913-Thrombelastography, pubmed-meshheading:20539913-Time Factors, pubmed-meshheading:20539913-Venous Thrombosis
pubmed:year
2010
pubmed:articleTitle
FIX-Triple, a gain-of-function factor IX variant, improves haemostasis in mouse models without increased risk of thrombosis.
pubmed:affiliation
Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't