Empty Capsids and Macrophage Inhibition/Depletion Increase rAAV Transgene Expression in Joints of Both Healthy and Arthritic Mice.
Gene therapy has potential to treat rheumatic diseases; however, the presence of macrophages in the joint might hamper adeno-associated viral vector-mediated gene delivery. Here we demonstrate that in arthritic, but also in healthy, mice administration of agents that influence macrophage activity/number and/or addition of empty decoy capsids substantially improve the efficacy of recombinant adeno-associated viral vector 5 transgene expression in the joint. Pretreatment with triamcinolone or clodronate liposomes improved luciferase expression over a period of 4 weeks. Similar results were seen when empty decoy capsids were added to full genome containing capsids in a 5:1 ratio. In a study to assess the duration of expression as well as to investigate the combination of these two approaches, we observed a synergistic enhancement of gene expression, sustained for at least 12 weeks. The enhancement of gene expression was independent of the route of administration of triamcinolone (intra-articular or intramuscular). In healthy mice it was demonstrated that the combination improved expression of the transgene significantly, in a serotype independent manner. These data have implications for future applications of gene therapy to the joint and for other tissues with an abundance of macrophages.
1 Arthrogen B.V. , Amsterdam, the Netherlands.|2 Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam , the Netherlands.
Caroline J
CJ
Aalbers
1 Arthrogen B.V. , Amsterdam, the Netherlands.
Niels
N
Broekstra
1 Arthrogen B.V. , Amsterdam, the Netherlands.
Mariska
M
van Geldorp
1 Arthrogen B.V. , Amsterdam, the Netherlands.
Emiel
E
Kramer
3 Department of Rheumatology, Leiden University Medical Center , Leiden, the Netherlands .
Sofia
S
Ramiro
1 Arthrogen B.V. , Amsterdam, the Netherlands.|2 Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam , the Netherlands.
Paul P
PP
Tak
1 Arthrogen B.V. , Amsterdam, the Netherlands.|2 Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam , the Netherlands.
Margriet J
MJ
Vervoordeldonk
1 Arthrogen B.V. , Amsterdam, the Netherlands.|2 Division of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam , the Netherlands.
Jonathan D
JD
Finn
D000818:Animals; D001168:Arthritis / Q000235:genetics / Q000628:therapy*; D002213:Capsid / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007596:Joints / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D019076:Transgenes / Q000502:physiology*
AAV; arthritis; empty capsid; gene therapy; immune suppression; macrophages