Improved anti‐cancer effect of interferon gene transfer by sustained expression using CpG‐reduced plasmid DNA

Kawano, Hiroyuki; Nishikawa, Makiya; Mitsui, Masaru; Takahashi, Yuki; Kako, Keiko; Yamaoka, Kiyoshi; Watanabe, Yoshihiko; Takakura, Yoshinobu

doi:10.1002/ijc.22636

Cited by 32 publications

(38 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28 Furthermore, the reduction in the number of CpG motifs was linked with the prolonged transgene expression from the vectors delivered by hydrodynamic injection, suggesting that CpG-depleted plasmid vectors are useful for sustained transgene expression. 11,12 Even though this conclusion seems to be valid in terms of safety or reduced cytokine production, especially when lipoplex is used for transfection, 29 our previous study rejected the hypothesis that pro-inflammatory cytokines inhibit transgene expression from plasmid vectors. 12 In our previous study, 10 the lipoplex-induced pro-inflammatory cytokines, such as tumor necrosis factor-a, IFN-g and interleukin-12, did not reduce transgene expression from plasmid vectors.…”

Section: Discussionmentioning

confidence: 94%

“…[8][9][10] To achieve long-term expression of IFN-g, we developed plasmid vectors that express murine IFN-g (Mug) for a long period of time. 11,12 A single administration of the newly constructed IFN-gexpressing plasmids by the hydrodynamic injection method, which is a most efficient method for in vivo gene transfer, 13 was effective in obtaining therapeutic levels of IFN-g over 480 days and in exerting marked therapeutic effects in various diseases models, including metastatic tumor and atopic dermatitis. 11,12,14 In these studies, transient expression of IFN-g showed little therapeutic effect, emphasizing the importance of sustained expression.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

et al. 2011

View full text Add to dashboard Cite

Sustained expression of murine interferon (IFN)-g (Mug) was found to be effective in preventing tumor metastasis and atopic dermatitis in mouse models. However, our preliminary experiments suggested that the time-dependent decrease in the Mug expression was not compensated for by repeated injections of Mug-expressing plasmid. To identify the mechanism underlying this observation, a reporter plasmid was hydrodynamically injected into mice and the levels of the plasmid, mRNA and reporter protein were measured in mice receiving a pre-or co-administration of Mug-expressing plasmid. Co-injection of Mug-expressing plasmid had no significant effects on transgene expression from the reporter plasmid. In contrast, pre-injection of Mugexpressing plasmid greatly inhibited the expression of the reporter protein. Moreover, pre-injection of Mug-expressing plasmid also reduced the amount of the reporter plasmid in the nuclear fraction of mouse liver to o10%, and that of reporter mRNA to o1%. The degree of reduction in the expression of reporter protein was comparable with the reduction in mRNA. These results indicate that the difficulty in regaining the expression level of IFN-g is due to the impaired delivery of plasmid to the nucleus and to the suppression of transcription from the plasmid.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

et al. 2011

View full text Add to dashboard Cite

show abstract

“…36 Targeting PC by molecular abnormality remains elusive because of the accumulation of multiple genetic changes during its multistep carcinogenesis. During the last decade, numerous studies illustrated the gene transfer or systemic delivery of IFN-b to inhibit tumor growth in multiple animal models from gliomas, 37 to hepatocellular carcinoma, 38 metastatic breast cancer, 39 prostate cancer, [40][41][42] rectum, colon and endometrial tumors, [43][44][45] lung tumors, 46,47 renal cell carcinomas and melanoma, 48,49 neuroblastoma, 50,51 disseminated peritoneal cancer, 52 bladder cancer, 53 malignant mesothelia 54 and fibrosarcomas. 55 Recently, a cancer gene therapy trial for gliomas based on the intratumoral administration of IFN-b) was shown to be feasible and associated with apoptosis induction.…”

Section: Lentiviral Vectors For Pc Therapy E Ravet Et Almentioning

confidence: 99%

Using lentiviral vectors for efficient pancreatic cancer gene therapy

et al. 2009

View full text Add to dashboard Cite

Pancreatic cancer (PC) remains a life-threatening disease. Efficient therapeutic gene delivery to PC-derived cells continues to present challenges. We used self-inactivated lentiviral vectors to transduce PC-derived cells in vitro and in vivo. We showed that lentiviral vectors transduce PC-derived cell lines with high efficiency (490%), regardless of the differentiation state of the cell. Next, we transferred human interferon beta (hIFN-b) gene. Expression of hIFN-b in PC cells using lentiviral vectors resulted in the inhibition of cell proliferation and the induction of cell death by apoptosis. In vivo, lentiviral administration of hIFN-b prevented PC tumor progression for up to 15 days following gene therapy, and induced tumor regression/stabilization in 50% of the mice treated. Again, hIFN-b expression resulted in cancer cell proliferation inhibition and apoptosis induction. We provide evidence that human immunodeficiency virus (HIV)-1-based lentiviral vectors are very efficient for gene transfer in PC-derived cells in vitro and in vivo. As a consequence, delivery of hIFN-b stopped PC tumor progression. Thus, our approach could be applied to the 85% of PC patients with a locally advanced disease.

show abstract

“…In addition to these challenges, gene delivery is an option to increase the in vivo half-life of therapeutic proteins, including IFNs. In previous studies, we proved that the depletion of CpG motifs in plasmid vectors is an effective approach for extending the duration of transgene expression (20,21). We also succeeded in developing a murine IFN-g-expressing plasmid DNA, pCpGMug, which contains no CpG motifs except for those in the cDNA region (22).…”

mentioning

confidence: 99%

“…In this study, we injected pCpG-Mug, a murine IFN-g-expressing plasmid DNA, into a human atopic dermatitis model (NC/Nga mice) (23), to achieve a sustained transgene expression of IFN-g. A conventional CpG replete plasmid vector expressing IFN-g, pCMVMug (21,24), was also used for comparison to examine the importance of the duration of transgene expression on the immunological changes induced by IFN-g gene transfer. The expression profile of IFN-g was first examined in NC/Nga mice, and the effect of the expression on the level of IL-4, -5, -10, -12, -13, -17, and thymus and activation-regulated chemokine (TARC) was evaluated.…”

mentioning

confidence: 99%

Sustained Exogenous Expression of Therapeutic Levels of IFN-γ Ameliorates Atopic Dermatitis in NC/Nga Mice via Th1 Polarization

Hattori

Nishikawa²,

Watcharanurak³

et al. 2010

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The short in vivo half-life of IFN-γ can prevent the cytokine from inducing immunological changes that are favorable for the treatment of Th2-dominant diseases, such as atopic dermatitis. To examine whether a sustained supply of IFN-γ is effective in regulating the balance of Th lymphocyte subpopulations, plasmid vector encoding mouse IFN-γ, pCpG-Muγ, or pCMV-Muγ was injected into the tail vein of NC/Nga mice, a model for human atopic dermatitis. A single hydrodynamic injection of a CpG motif reduced pCpG-Muγ at a dose of 0.14 μg/mouse resulted in a sustained concentration of IFN-γ in the serum, and the concentration was maintained at >300 pg/ml over 80 d. The pCpG-Muγ–mediated IFN-γ gene transfer was associated with an increase in the serum concentration of IL-12, reduced production of IgE, and inhibition of mRNA expression of IL-4, -5, -10, -13, and -17 and thymus and activation-regulated chemokine in the spleen. These immunological changes were not clearly observed in mice receiving two injections of 20 μg pCMV-Muγ, a CpG-replete plasmid DNA, because of the transient nature of the expression from the vector. The mice receiving pCpG-Muγ showed a significant reduction in the severity of skin lesions and in the intensity of their scratching behavior. Furthermore, high transepidermal water loss, epidermal thickening, and infiltration of lymphocytes and eosinophils, all of which were obvious in the untreated mice, were significantly inhibited. These results indicate that an extraordinary sustained IFN-γ expression induces favorable immunological changes, leading to a Th1-dominant state in the atopic dermatitis model.

show abstract

Improved anti‐cancer effect of interferon gene transfer by sustained expression using CpG‐reduced plasmid DNA

Cited by 32 publications

References 36 publications

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

Inhibition of nuclear delivery of plasmid DNA and transcription by interferon γ: hurdles to be overcome for sustained gene therapy

Using lentiviral vectors for efficient pancreatic cancer gene therapy

Sustained Exogenous Expression of Therapeutic Levels of IFN-γ Ameliorates Atopic Dermatitis in NC/Nga Mice via Th1 Polarization

Contact Info

Product

Resources

About