TY - JOUR
T1 - Empty Capsids and Macrophage Inhibition/Depletion Increase rAAV Transgene Expression in Joints of Both Healthy and Arthritic Mice
AU - Aalbers, Caroline J.
AU - Broekstra, Niels
AU - van Geldorp, Mariska
AU - Kramer, Emiel
AU - Ramiro, Sofia
AU - Tak, Paul P.
AU - Vervoordeldonk, Margriet J.
AU - Finn, Jonathan D.
PY - 2017
Y1 - 2017
N2 - 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
AB - 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
U2 - https://doi.org/10.1089/hum.2016.036
DO - https://doi.org/10.1089/hum.2016.036
M3 - Review article
C2 - 27806641
SN - 1043-0342
VL - 28
SP - 168
EP - 178
JO - Human gene therapy
JF - Human gene therapy
IS - 2
ER -