Nonviral Approaches Satisfying Various Requirements for Effective in Vivo Gene Therapy.

Nishikawa, Makiya; Hashida, Mitsuru

doi:10.1248/bpb.25.275

Cited by 94 publications

(56 citation statements)

References 117 publications

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“…Although, these vaccines effectively decreased A␤ depositions in the brains of model mice, the possibility of viral replication could not be completely excluded. The plasmid vector is safe and has no possibility of viral infection and transformation because it exists as an episome without being built into the chromosome in eukaryotic cells (12,13). Another important factor is related to technology.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Okura

Miyakoshi

Kohyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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It was recently demonstrated that amyloid ␤ (A␤) peptide vaccination was effective in reducing the A␤ burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-A␤ antibody therapy and other types of vaccination are now in trial. In this study, we have developed safe and effective nonviral A␤ DNA vaccines against Alzheimer's disease. We administered these vaccines to model (APP23) mice and evaluated A␤ burden reduction. Prophylactic treatments started before A␤ deposition reduced A␤ burden to 15.5% and 38.5% of that found in untreated mice at 7 and 18 months of age, respectively. Therapeutic treatment started after A␤ deposition reduced A␤ burden toϷ50% at the age of 18 months. Importantly, this therapy induced neither neuroinflammation nor T cell responses to A␤ peptide in both APP23 and wild-type B6 mice, even after long-term vaccination. Although it is reported that other anti-A␤ therapies have pharmacological and͞or technical difficulties, nonviral DNA vaccines are highly secure and easily controllable and are promising for the treatment of Alzheimer's disease. (4) and the passive transfer of anti-A␤ antibodies were also effective in reducing amyloid deposits (5). Moreover, vaccinated mice showed an improvement in memory loss (6, 7). Thus, A␤ peptide vaccine therapy has been shown to be effective in animal models, and human clinical trials were started with Betabloc (AN-1792), composed of synthetic A␤1-42 and QS21 as an adjuvant (8). However, the phase II clinical trial was halted because of the development of acute meningoencephalitis that appeared in 18 (6%) of 298 vaccinated patients (9). Importantly, it was later demonstrated by autopsy that there was a significant reduction of amyloid deposition and disappearance of degenerative axons in a treated patient (10). At the same time, T cell-dominant meningeal encephalitis was present in the cerebral cortex. These findings suggest that the vaccine therapy is a promising strategy for human Alzheimer's disease if excessive immune reactions are minimized to avoid unwanted neuroinflammation.Recently, it was reported that naked plasmid DNAs encoding proteins are taken into cells and produce the proteins in a small amount for a relatively long period when injected into the muscle or skin (11). Then, the proteins that are released in the extracellular space induce antibodies against the proteins (12, 13). Thus, gentle and quiet immune reactions could be obtained by DNA vaccine administration. In our and other's laboratories, immune therapies with DNA vaccines have been examined in autoimmune disease models (14-17) and have been found to be effective in preventing the diseases without the use of adjuvants. Here, we developed nonviral A␤ DNA vaccines and were able to reduce the amyloid burden in the cerebral cortex and hippocampus of Alzheimer's disease model (APP23) mice by vaccination. Importantly, the side effects, such as T cell proliferation and neuroin...

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Section: Discussionmentioning

confidence: 99%

“…Then, the proteins that are released in the extracellular space induce antibodies against the proteins (12,13). Thus, gentle and quiet immune reactions could be obtained by DNA vaccine administration.…”

mentioning

confidence: 99%

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Okura

Miyakoshi

Kohyama

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Although plasmid DNA (pDNA), the most frequently-used nonviral vector, avoids the fatal disadvantages that have been experienced with viral vectors, such as virus-induced acute organ failure and insertional mutagenesis, its transgene expression characteristics need to be improved for effective in vivo gene therapy. 1,2 The low level of transgene expression has been unacceptable in pDNA-based nonviral vectors for many years, but the development of highly effective nonviral gene delivery methods has now almost solved the problem. The application of electric pulses or ultrasound can significantly increase the level of transgene expression up to 100-fold or more in various experimental settings.…”

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confidence: 99%

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

Kawano

Nishikawa

Mitsui

et al. 2007

Intl Journal of Cancer

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Plasmid DNA (pDNA) expressing mouse interferon (IFN)-b or IFN-c (pCMV-Mub and pCMV-Muc, respectively) has been shown to be effective in inhibiting the growth of colon carcinoma CT-26 cells in the liver (Kobayashi et al., Molecular Therapy 2002;6:737-44). The therapeutic effect of such IFN gene transfer could be significantly increased by the sustained expression of IFNs. In the present study, CpG-reduced pDNA encoding IFN-b or IFN-c (pGZB-Mub and pGZB-Muc, respectively) was constructed. pCMV-Mub and pCMV-Muc were used as conventional CpG-replete pDNAs. Each pDNA was injected into the tail vein of mice by the hydrodynamics-based procedure. An injection of pGZB-Mub resulted in very high IFN-b activities in the serum for at least 24 hr after injection, whereas the IFN-b activity after pCMV-Mub injection declined quickly. About a 14-fold greater amount of IFN-b was produced from pGZB-Mub than from pCMV-Mub. pGZB-Mub markedly inhibited the pulmonary metastasis of CT-26 cells. Similar, but more marked results were obtained with pGZB-Muc: it increased the area under the concentration-time curve by more than a 60-fold and the mean residence time of IFN-c 4-fold compared with pCMV-Muc. The survival time of the pGZB-Muc-treated mice was significantly (p < 0.05) longer than that of the saline-or pCMV-Muc-treated mice. These results indicate that long-term expression of IFN can be achieved by CpG-reduced pDNA and sustained IFN gene expression results in enhanced therapeutic effects of IFN gene transfer against tumor metastasis. ' 2007 Wiley-Liss, Inc.

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“…Several studies have been performed to investigate treatment of gastric ulcer [2] and gastric cancer [3]. The in vivo gene delivery systems can be categorized as viral [4] and non-viral approaches [5]. Although non-viral vectors generally have a problem in terms of transfection efficiency, non-viral vectors have safety advantages compared with viral vectors.…”

Section: Introductionmentioning

confidence: 99%

Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice

Nishi

Fumoto

Ishii

et al. 2008

European Journal of Pharmaceutics and Biopharmaceutics

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Stomach-selective gene transfer is a promising approach as a therapeutic strategy for refractory gastric diseases. In this study, we improved the stomach selectivity of gene expression following microinstillation of naked plasmid DNA (pDNA) onto the gastric serosal surface in mice. pDNA encoding firefly luciferase was used as a reporter gene. It was confirmed that the gene expression level in the stomach 6 h after gastric serosal surface microinstillation of pDNA was significantly higher than after intragastric, intraperitoneal and intravenous administration. Regarding selectivity of gene expression, the gene expression level in the stomach after gastric serosal surface microinstillation of 1 µg/1 µL (dose/volume) pDNA was 5.7 times higher than that in the spleen. In our previous study (30 µg/30 µL), the expression level in the stomach was 2.7 times higher than that in the spleen; therefore, the selectivity was 2.1 times higher in this study. When we investigated gene expression at various pDNA solution concentrations, the ratio of the gene expression level in the stomach to that in the spleen was the highest as 1 µg/1 µL of pDNA, which was considered the optimal concentration. Information in this study is useful for further development of target organ-selective gene delivery systems.

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Nonviral Approaches Satisfying Various Requirements for Effective in Vivo Gene Therapy.

Cited by 94 publications

References 117 publications

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

Nonviral Aβ DNA vaccine therapy against Alzheimer’s disease: Long-term effects and safety

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

Improved stomach selectivity of gene expression following microinstillation of plasmid DNA onto the gastric serosal surface in mice

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