Enhanced gene transfer to arthritic joints using adeno-associated virus type 5: implications for intra-articular gene therapy

Adriaansen, Janik; Tas, Sander W.; Klarenbeek, Paul L.; Bakker, Andrew C.; Apparailly, Florence; Firestein, Gary S.; Jørgensen, Christian; Vervoordeldonk, Margriet J.; Tak, Paul P.

doi:10.1136/ard.2004.035063

Cited by 59 publications

(47 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Transduction efficiencies reached up to 95%, even when using relatively low MOI and vector doses (MOI = 6-20 in vitro; 4 × 10 8 functional recombinant particles in situ), probably because of the high permissivity of the cells to rAAV transduction and to their ability to rapidly process the viral particles compared with fibroblasts, which require much higher amounts of rAAV (MOI of at least 2,000) to allow for an efficient viral trafficking to the nucleus and to detectable transgene expression, in good agreement with previous findings (20,27,31,45,(60)(61)(62). Interestingly, transgene expression was seen throughout the thickness of the cartilage, probably because of the ability of the small rAAV particles to penetrate the dense cartilage matrix and in agreement with previous findings using this class of vector (20,27,45 (65).…”

Section: Discussionsupporting

confidence: 77%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

View full text Add to dashboard Cite

Administration of therapeutic genes to human osteoarthritic (OA) cartilage is a potential approach to generate effective, durable treatments against this slow, progressive disorder. Here, we tested the ability of recombinant adeno-associated virus (rAAV)-mediated overexpression of human insulinlike growth factor (hIGF)-I to reproduce an original surface in human OA cartilage in light of the pleiotropic activities of the factor. We examined the proliferative, survival and anabolic effects of the rAAV-hIGF-I treatment in primary human normal and OA chondrocytes in vitro and in explant cultures in situ compared with control (reporter) vector delivery. Efficient, prolonged IGF-I secretion via rAAV stimulated the biological activities of OA chondrocytes in all the systems evaluated over extended periods of time, especially in situ, where it allowed for the long-term reconstruction of OA cartilage (at least for 90 d). Remarkably, production of high, stable amounts of IGF-I in OA cartilage using rAAV advantageously modulated the ex-

show abstract

Section: Discussionsupporting

confidence: 77%

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Weimer

Madry

Venkatesan

et al. 2011

Mol Med

View full text Add to dashboard Cite

show abstract

“…Briefly, in experiments to assess leukocyte rolling and adhesion, HUVEC monolayers were treated or not with TNF (0.03 ng/ml) for 4 h. Blood collected from healthy volunteers was then diluted 1:10 in HBSS and perfused over the HUVEC monolayer for 5 min at a flow rate of 150 s 21 . Subsequently, blood was replaced with HBSS to clear the field, 8-12 random fields (0.23 mm 2 /field) were recorded for 10 s each, and the numbers of rolling and adherent (static for .10 s) leukocytes were determined on playback analysis.…”

Section: Flow Chamber Assaymentioning

confidence: 99%

“…Scott Loiler (Arthrogen, Amsterdam, The Netherlands) and Margriet Vervoordeldonk (Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands) was used (21). Stably transfected NF-kB reporter HMECs, generated as described above, were plated in a 96-well plate (2 3 10 4 /well) and allowed to adhere overnight.…”

Section: Construction and Infection Of Gilz-recombinant Adeno-associamentioning

confidence: 99%

GILZ Overexpression Inhibits Endothelial Cell Adhesive Function through Regulation of NF-κB and MAPK Activity

Cheng

Fan

Ngo

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF-stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-κB activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-κB p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-κB p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment.

show abstract

“…108 Furthermore, several naturally occurring AAV serotypes exists, each of which displays a different tropism, potentially allowing vector selection to be tailored to target expression in particular tissues in vivo. 109,110 As NF-κB is ubiquitously expressed in human cells, this characteristic could help to reduce off-target effects and unwanted side effects. Another option is ex vivo gene transfer, which could remove the need for viral vectors altogether.…”

Section: Targeting Iκb Proteinsmentioning

confidence: 99%

Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

2016

View full text Add to dashboard Cite

Autoimmune diseases arise from the loss of tolerance to endogenous self-antigens, resulting in a heterogeneous range of chronic conditions that cause considerable morbidity and mortality worldwide. In Western countries, over 5% of the population is affected by some form of autoimmune disease, with enhanced or inappropriate activation of nuclear factor (NF)–κB implicated in a number of these conditions. Although treatment strategies for autoimmunity have improved significantly in recent years, current therapeutics are still not capable of achieving satisfactory disease management in all patients, and as such, the therapeutic modulation of NF-κB is an attractive target in autoimmunity. To date, no NF-κB inhibitors have progressed to the clinic for the treatment of autoimmunity, but a variety of promising approaches targeting multiple stages of the NF-κB pathway are currently being explored. This review focuses on the current strategies being investigated for the inhibition of the NF-κB pathway in autoimmune diseases and considers potential future strategies for the therapeutic targeting of this crucial transcription factor.

show abstract

Enhanced gene transfer to arthritic joints using adeno-associated virus type 5: implications for intra-articular gene therapy

Cited by 59 publications

References 42 publications

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

Benefits of Recombinant Adeno-Associated Virus (rAAV)-Mediated Insulinlike Growth Factor I (IGF-I) Overexpression for the Long-Term Reconstruction of Human Osteoarthritic Cartilage by Modulation of the IGF-I Axis

GILZ Overexpression Inhibits Endothelial Cell Adhesive Function through Regulation of NF-κB and MAPK Activity

Modulation of NF-κB Signaling as a Therapeutic Target in Autoimmunity

Contact Info

Product

Resources

About