Contribution of Plasmid DNA to Hepatotoxicity after Systemic Administration of Lipoplexes

Loisel, Séverine; Gall, Catherine Le; Doucet, Laurent; Férec, Claude; Floch, Virginie

doi:10.1089/104303401300057405

Cited by 93 publications

(51 citation statements)

References 23 publications

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“…Animals that survive this initial shock eventually succumb from continued lung reaction and mounting liver toxicity. 9,41 These later toxic effects may be mediated through the same blood effects but also via activation of macrophages and other non-parenchymal cells in these organs (in particular Kupffer cells) after uptake of large amounts of cationic DNA complexes. 9 The importance of CpG DNA sequences lends credence to the role of DNA uptake in the systemic toxicity of cationic DNA complexes.…”

Section: Discussionmentioning

confidence: 99%

Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery

et al. 2003

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The intravenous delivery of plasmid DNA complexed with either cationic lipids (CL) or polyethyleneimine (PEI) enables high levels of foreign gene expression in lung. However, these cationic DNA complexes cause substantial toxicity. The present study found that the inclusion of polyacrylic acid (pAA) with DNA/polycation and DNA/CL complexes prevented the serum inhibition of the transfection complexes in cultured cells. The mechanism mediating this increase seems to involve both particle size enlargement due to flocculation and electrostatic shielding from opsonizing serum proteins. The use of pAA also increased the levels of lung expression in mice in vivo substantially above the levels achieved with just binary complexes of DNA and linear PEI (lPEI) or CL and reduced their toxicity. Also, the use of a 'chaser' injection of pAA 30 min after injection of the ternary DNA/lPEI/pAA complexes further aided this effort to reduce toxicity while not affecting foreign gene expression. By optimizing the amount of pAA, lPEI, and DNA within the ternary complexes and using the 'chaser' injection, substantial levels of lung expression were obtained while avoiding adverse effects in lung or liver. These developments will aid the use of cationic DNA complexes in animals and for eventual human gene therapy.

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Section: Discussionmentioning

confidence: 99%

Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery

et al. 2003

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“…Systemically administered plasmid vectors can also induce hepatotoxicity and both humoral and cell-mediated immune responses that limit their application in vivo, an effect most frequently observed when viral promoters such as CMV are used to drive transgene expression [Loisel et al, 2001;Tousignant et al, 2000]. Studies have indicated that inflammation associated with plasmid DNA may be due to the presence of particular unmethylated C⋅G dinucleotides ('CpG-S DNA') (reviewed in [Krieg, 1999]).…”

Section: Viral Promoters In Plasmid Vectorsmentioning

confidence: 99%

Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy

Papadakis

Nicklin²,

Baker³

et al. 2004

CGT

145

121

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It has become apparent that the clinical success anticipated in the field of gene therapy has been limited by progress in several of the fundamental areas of genetics, molecular and cellular biology relevant to its application. Whilst a great deal of effort has been made in the evaluation of transgenes, it is only more recently with the advance of vector systems that attention has begun to be focused upon the means and control of transgene expression. Until recently, the majority of constructs have employed ubiquitous viral promoters to drive expression from simple gene expression cassettes using viral promoters and lacking introns, 3' untranslated regions (UTRs), locus control regions (LCR's), matrix attachment regions (MAR's) and other such genetic components. It has consequently emerged that these elements may have a key role in determining the levels and longevity of gene expression attainable in vivo, irrespective of the vector system utilised. The majority of gene therapy applications would also benefit from the specific optimisation of 'tailormade' expression cassettes to optimise their therapeutic efficacy. In conjunction with modification of vector tropism and strategies to limit their immunogenicity, this should create vectors suitable for the clinical application of gene therapy. This review aims to highlight some of the principle considerations of gene expression in vivo, and the means by which it may most effectively be achieved, whether this is via the minimal modification of an existing eukaryotic promoter or by the more extensive design of a novel promoter and associated elements.

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“…3 Moreover, the intravenous injection of cationic liposome/pDNA complexes causes proinflammatory cytokine-induced hepatic toxicity because of the recognition of Toll-like receptor 9 to CpG motifs in the pDNA sequence that upregulate the activation of transcription factors, such as nuclear factor-kB (NF-kB), thereby contributing to the production of proinflammatory cytokines from liver macrophages. [4][5][6][7][8] Therefore, an approach to enhance the antitumor efficacy and reduce the toxicity of cationic liposome/IL-12 pDNA complexes for treatment of metastatic lung tumors is required. Combination therapy has been used to increase the antitumor efficacy and reduce the systemic toxicity of IL-12.…”

Section: Introductionmentioning

confidence: 99%

Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

et al. 2010

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Interleukin 12 (IL-12) is a proinflammatory cytokine with antitumor activity. All-trans-retinoic acid (ATRA) exerts antitumor effects by regulating a variety of gene expressions, including tumor necrosis factor receptor 1 (TNFR1), increases the number of TNFR1 and potentiates TNF-a-induced apoptosis in cancer cells. In this study, ATRA-incorporated cationic liposome (ATRA-cationic liposome)/ IL-12 plasmid DNA (pDNA) complexes were prepared to improve therapeutic efficacy of cationic liposome/IL-12 pDNA complexes in a mouse model of metastatic lung tumor after intravenous injection. IL-12 production in lungs by ATRA-cationic liposome/IL-12 pDNA complexes was comparable with that by cationic liposome/IL-12 pDNA complexes. The number of metastatic tumor cells (colon26/Luc) was quantitatively evaluated by measuring luciferase activity. ATRA-cationic liposome/IL-12 pDNA complexes reduced the number of colon26/Luc cells and tumor nodules in lungs. ATRA-cationic liposome/IL-12 pDNA complexes significantly prolonged the survival time of mice, whereas cationic liposome/IL-12 pDNA only slightly prolonged it. ATRA-cationic liposome/IL-12 pDNA complexes increased the TNFR1 mRNA upregulation and the number of apoptotic cells in the lung. Moreover, reduced serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were observed in mice treated with ATRA-cationic liposome/IL-12 pDNA complexes. These results suggest that intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes is an effective method for the treatment of lung metastasis in mice.

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Contribution of Plasmid DNA to Hepatotoxicity after Systemic Administration of Lipoplexes

Cited by 93 publications

References 23 publications

Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery

Recharging cationic DNA complexes with highly charged polyanions for in vitro and in vivo gene delivery

Promoters and Control Elements: Designing Expression Cassettes for Gene Therapy

Enhanced growth inhibition of metastatic lung tumors by intravenous injection of ATRA-cationic liposome/IL-12 pDNA complexes in mice

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