Activated factor X delivered by adeno-associated virus significantly inhibited bleeding and alleviated hemophilic synovitis in hemophilic mice

In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and...

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Bibliographic Details
Published in:Gene therapy 2024-11, Vol.31 (11-12), p.544-552
Main Authors: Zhang, Feixu, Zhou, Xinyue, Hua, Baolai, He, Xinyi, Li, Zhanao, Xiao, Xiao, Wu, Xia
Format: Article
Language:English
Subjects:
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692/699/1541
Adenoviruses
Animals
Biomedical and Life Sciences
Biomedicine
Bleeding
Cell Biology
Coagulation
Coagulation factors
Dependovirus - genetics
Disease Models, Animal
Factor Xa - metabolism
Gene Expression
Gene Therapy
Genetic Therapy - methods
Genetic Vectors - administration & dosage
Genetic Vectors - genetics
Hemophilia
Hemophilia A - complications
Hemophilia A - therapy
Hemophilia B - complications
Hemophilia B - therapy
Hemorrhage - etiology
Hemorrhage - therapy
Human Genetics
Humans
Inflammation
Mice
Nanotechnology
Synovitis
Synovitis - etiology
Synovitis - therapy
Thrombin
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Summary:In hemophilia, deficiency of factor VIII or IX prevents the activation of the common coagulation pathway, and inhibits the conversion of FX to activated FXa, which is required for thrombin generation. We hypothesized that the direct expressed FXa has the potential to activate the common pathway and restore coagulation in hemophilia patients. In this study, the cassettes that expressed FXa, FXaop and FXa-FVII were packaged into an engineered AAV capsid, AAV843, and were delivered into hemophilia A and B mice by intravenous injection. AAV-FXaop could be stably expressed in vivo and showed the best immediate and prolonged hemostatic effects, similar to those of commercial drugs (Xyntha and Benefix). AAV-FXaop also significantly inhibited bleeding in hemophilia A mice with inhibitors. In addition, FXa expression in joints significantly alleviated the occurrence of hemophilic synovitis. AAV-delivered FXa may be a novel target for treating hemophilic and hemophilic synovitis.
ISSN:0969-7128
1476-5462
1476-5462
DOI:10.1038/s41434-024-00479-5