A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis

Bakker, Andrew C.; Loo, Fons A. J. van de; Joosten, Leo A. B.; Bennink, Miranda B.; Arntz, Onno J.; Dmitriev, Igor; Kashentsera, E.A.; Curiel, David T.; Berg, Wim B. van den

doi:10.1038/sj.gt.3301612

Cited by 31 publications

(39 citation statements)

References 30 publications

(41 reference statements)

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“…Both adenoviral vectors were validated and gene transfer resulted in high production of sIL-1RAcP and IL-1Ra as described previously (24,35). Systemic overexpression of sIL1RAcP resulted in circulating amounts of sIL-1RAcP up to 900 ng/ml 3 days after injection of the adenoviral vector (24).…”

Section: Resultsmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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Objective. To discern the mode of interleukin-1 (IL-1) inhibition of soluble IL-1 receptor accessory protein (sIL-1RAcP) by comparison with IL-1 receptor antagonist (IL-1Ra) in arthritis.Methods. Adenoviral vectors encoding either sIL1RAcP or IL-1Ra were administered systemically before onset of collagen-induced arthritis in DBA/1 mice. Antibovine type II collagen IgG and IL-6 were quantified in serum. Proliferative response of splenic T cells was determined in the presence of sIL-1RAcP or IL-1Ra. The effect on IL-1 inhibition of recombinant sIL-1RAcP and IL-1Ra was further examined in vitro, using NF-B luciferase reporter cell lines. Quantitative polymerase chain reaction was used to determine the relative messenger RNA expression of the IL-1 receptors.Results. Adenoviral overexpression of both sIL1RAcP and IL-1Ra resulted in amelioration of the collagen-induced arthritis. Both IL-1 antagonists reduced the circulating levels of antigen-specific IgG2a antibodies, but only IL-1Ra was able to inhibit lymphocyte proliferation. By using purified lymphocyte populations derived from NF-B reporter mice, we showed that sIL-1RAcP inhibits IL-1-induced NF-B activity in B cells but not T cells, whereas IL-1Ra inhibited IL-1 on both cell types. A study in a panel of NF-B luciferase reporter cells showed that the sIL-1RAcP inhibits IL-1 signaling on cells expressing either low levels of membrane IL-1RAcP or high levels of IL-1RII.Conclusion. We show that the sIL-1RAcP ameliorated experimental arthritis without affecting T cell immunity, in contrast to IL-1Ra. Our results provide data in support of receptor competition by sIL-1RAcP as an explanation for the different mode of IL-1 antagonism in comparison with IL-1Ra.

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Section: Resultsmentioning

confidence: 99%

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Smeets¹,

Joosten²,

Arntz³

et al. 2005

Arthritis & Rheumatism

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“…Similar observations have been made after intra-articular treatment of CIA with IL-1 receptor antagonist, which also results in amelioration of the CIA in the distal paws of treated mice. 25,26 Whether these effects are the result of a direct local inhibition of cytokine spillover and antigen release by reduced inflammation or caused by leakage of IL18BPc to distal joints remains to be established. When comparing incidence versus severity in the distal paws of IL-18BP-treated animals, IL-18 significantly reduced incidence while increase in severity of affected hind paws could not be halted.…”

Section: Discussionmentioning

confidence: 99%

“…24 Therefore, in some situations it appears preferable to choose local instead of systemic treatment. Studies by Bakker et al 25,26 already showed functionality of local intra-articular therapy for arthritis using IL-1 receptor antagonist.…”

Section: Introductionmentioning

confidence: 99%

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Smeets¹,

Loo²,

Arntz³

et al. 2003

Gene Ther

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“…13,14 When arthritis developed at 2 and 7 days after virus injection, luciferase activity was strongly increased (3.0 Â 10 4 RLU) ( Figure 1). As we described previously, 22 the transduction efficiency of the synovial tissue in arthritic joints was hampered. Still, luciferase activities were significantly increased over basal levels at day 2 and 7, although fiveto sixfold lower (5-6 Â 10 3 RLU) than activities observed in joints that were noninflamed at transduction.…”

Section: Il-1e/il-6p Promoter Is Responsive To Collagen-induced Arthrmentioning

confidence: 95%

Application of a disease-regulated promoter is a safer mode of local IL-4 gene therapy for arthritis

et al. 2007

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The application of disease-regulated promoters in local gene therapy for rheumatoid arthritis potentiates the development of a sophisticated treatment that relies on a restricted and fine-tuned supply of biologicals. Although several studies have investigated regulated promoters for achieving effective transgene expression during arthritis, none have explored their potential for minimizing deleterious effects arising from constitutive overexpression of transgenes under naive conditions. Using naive and collagen-induced arthritic mice, we examined the applicability of a hybrid interleukin-1 enhancer/interleukin-6 proximal promoter for achieving efficacious murine interleukin-4 gene therapy under arthritic conditions, while minimizing interleukin-4-induced inflammation under naive conditions. We found strong upregulation of transgene expression in virally transduced knee joints under arthritic conditions compared to levels in naive animals. Besides its responsiveness, the promoter strength proved sufficient for generating therapeutically efficacious levels interleukin-4, as demonstrated by the successful protection against cartilage erosion in collagen-induced arthritis. Most importantly, promoter-mediated restriction of the potent chemotactic interleukin-4 in naive animals strongly reduced the amounts of inflammatory cell influx. This study suggests the suitability of the interleukin-1 enhancer/interleukin-6 proximal promoter for the development of a local gene therapy strategy for rheumatoid arthritis that requires finetuned and restricted expression of transgenes with a pleiotrophic nature.

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A tropism-modified adenoviral vector increased the effectiveness of gene therapy for arthritis

Cited by 31 publications

References 30 publications

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Soluble interleukin‐1 receptor accessory protein ameliorates collagen‐induced arthritis by a different mode of action from that of interleukin‐1 receptor antagonist

Adenoviral delivery of IL-18 binding protein C ameliorates Collagen-Induced Arthritis in mice

Application of a disease-regulated promoter is a safer mode of local IL-4 gene therapy for arthritis

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