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Intraarticular factor IX protein or gene replacement protects against development of hemophilic synovitis in the absence of circulating factor IX.
- Source :
-
Blood [Blood] 2008 Dec 01; Vol. 112 (12), pp. 4532-41. Date of Electronic Publication: 2008 Aug 20. - Publication Year :
- 2008
-
Abstract
- Hemophilic bleeding into joints causes synovial and microvascular proliferation and inflammation (hemophilic synovitis) that contribute to end-stage joint degeneration (hemophilic arthropathy), the major morbidity of hemophilia. New therapies are needed for joint deterioration that progresses despite standard intravenous (IV) clotting factor replacement. To test whether factor IX within the joint space can protect joints from hemophilic synovitis, we established a hemophilia B mouse model of synovitis. Factor IX knockout (FIX(-/-)) mice received a puncture of the knee joint capsule with a needle to induce hemarthrosis; human factor IX (hFIX) was either injected through the needle into the joint space (intraarticularly) or immediately delivered IV. FIX(-/-) mice receiving intraarticular FIX protein were protected from synovitis compared with mice receiving same or greater doses of hFIX IV. Next, adeno-associated virus (AAV) gene transfer vectors expressing hFIX were injected into knee joints of FIX(-/-) mice. Joints treated with 10(10) vector genomes (vg)/joint AAV2-, AAV5-, or AAV8-hFIX or 2.5 x 10(9) vg/joint AAV5-hFIX developed significantly fewer pathologic changes 2 weeks after injury compared with the pathology of control injured contralateral hind limbs. Extravascular factor activity and joint-directed gene transfer may ameliorate hemophilic joint destruction, even in the absence of circulating FIX.
- Subjects :
- Animals
Biological Availability
Dependovirus genetics
Disease Models, Animal
Factor IX pharmacokinetics
Genetic Vectors
Hemophilia B blood
Hemophilia B complications
Hemophilia B pathology
Hemorrhage etiology
Hemorrhage prevention & control
Injections, Intra-Articular
Injections, Intravenous
Joint Diseases etiology
Joint Diseases prevention & control
Mice
Mice, Inbred C57BL
Mice, Knockout
Synovitis etiology
Factor IX administration & dosage
Factor IX genetics
Genetic Therapy
Hemophilia B therapy
Synovitis prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 112
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 18716130
- Full Text :
- https://doi.org/10.1182/blood-2008-01-131417